Dihydropyridinones and pyrrolinones useful as alpha 1A adrenoceptor antagonists

ABSTRACT

Novel dihydropyridinone and pyrrolinone compounds and pharmaceutically acceptable salts thereof are disclosed. The synthesis of these compounds and their use as alpha  1   a  adrenergic receptor antagonists is also described. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha  1   a  receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia can be achieved.

This application claims the benefit of U.S. Provisional Application No.60/106,095, filed Oct. 29, 1998 and U.S. Provisional Application No.60/141,463, filed Jun. 29, 1999.

FIELD OF THE INVENTION

This invention relates to certain dihydropyridinone and pyrrolinonecompounds and pharmaceutically acceptable salts thereof, theirsynthesis, and their use as alpha 1a adrenoceptor antagonists. Moreparticularly, the compounds of the present invention are useful fortreating benign prostatic hyperplasia (BPH).

References are made throughout this application to various publications,the disclosures of which are hereby incorporated by reference in theirentireties in order to more fully describe the state of the art to whichthis invention pertains.

BACKGROUND OF THE INVENTION

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors bind norepinephrine more strongly thanepinephrine and much more strongly than the synthetic compoundisoproterenol. The binding affinity of these hormones is reversed forthe beta receptors. In many tissues, the functional responses, such assmooth muscle contraction, induced by alpha receptor activation areopposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into alpha 1, alpha 2, β₁, and β₂ subtypes. Functionaldifferences between alpha 1 and alpha 2 receptors have been recognized,and compounds which exhibit selective binding between these two subtypeshave been developed.

For a general background on the alpha adrenergic receptors, the reader'sattention is directed to Robert R. Ruffolo, Jr., a-Adrenoreceptors:Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic andClinical Pharmacology series, Karger, 1991), wherein the basis of alpha1/alpha 2 subclassification, the molecular biology, signal transduction(G-protein interaction and location of the significant site for this andligand binding activity away from the 3′-terminus of alpha adrenergicreceptors), agonist structure-activity relationships, receptorfunctions, and therapeutic applications for compounds exhibitingalpha-adrenergic receptor affinity was explored.

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the alpha 1 receptorsinto alpha 1d (formerly known as alpha 1a or 1a/1d), alpha 1b and alpha1a (formerly known as alpha 1c) subtypes. Each alpha 1 receptor subtypeexhibits its own pharmacologic and tissue specificities. The designation“alpha 1a” is the appellation recently approved by the IUPHARNomenclature Committee for the previously designated “alpha 1c” clonedsubtype as outlined in the 1995 Receptor and Ion Channel NomenclatureSupplement (Watson and Girdlestone, 1995). The designation alpha 1a isused throughout this application to refer to this subtype. At the sametime, the receptor formerly designated alpha 1a was renamed alpha 1d.The new nomenclature is used throughout this application. Stable celllines expressing these alpha 1 receptor subtypes are referred to herein;however, these cell lines were deposited with the American Type CultureCollection (ATCC) under the old nomenclature. For a review of theclassification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel,et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10.

The differences in the alpha adrenergic receptor subtypes have relevancein pathophysiologic conditions. Benign prostatic hyperplasia, also knownas benign prostatic hypertrophy or BPH, is an illness typicallyaffecting men over fifty years of age, increasing in severity withincreasing age. The symptoms of the condition include, but are notlimited to, increased difficulty in urination and sexual dysfunction.These symptoms are induced by enlargement, or hyperplasia, of theprostate gland. As the prostate increases in size, it impinges onfree-flow of fluids through the male urethra. Concommitantly, theincreased noradrenergic innervation of the enlarged prostate leads to anincreased adrenergic tone of the bladder neck and urethra, furtherrestricting the flow of urine through the urethra.

In benign prostatic hyperplasia, the male hormone5alpha-dihydrotestosterone has been identified as the principal culprit.The continual production of 5a-dihydrotestosterone by the male testesinduces incremental growth of the prostate gland throughout the life ofthe male. Beyond the age of about fifty years, in many men, thisenlarged gland begins to obstruct the urethra with the pathologicsymptoms noted above.

The elucidation of the mechanism summarized above has resulted in therecent development of effective agents to control, and in many casesreverse, the pernicious advance of BPH. In the forefront of these agentsis Merck & Co., Inc.'s product PROSCAR® (finasteride). The effect ofthis compound is to inhibit the enzyme testosterone 5-a reductase, whichconverts testosterone into 5a-dihydrotesterone, resulting in a reducedrate of prostatic enlargement, and often reduction in prostatic mass.

The development of such agents as PROSCAR® bodes well for the long-termcontrol of BPH. However, as may be appreciated from the lengthydevelopment of the syndrome, its reversal also is not immediate. In theinterim, those males suffering with BPH continue to suffer, and may infact lose hope that the agents are working sufficiently rapidly.

In response to this problem, one solution is to identifypharmaceutically active compounds which complement slower-actingtherapeutics by providing acute relief. Agents which induce relaxationof the lower urinary tract tissue, by binding to alpha 1 adrenergicreceptors, thus reducing the increased adrenergic tone due to thedisease, would be good candidates for this activity. Thus, one suchagent is alfuzosin, which is reported in EP 0 204597 to induce urinationin cases of prostatic hyperplasia. Likewise, in WO 92/00073, theselective ability of the R(+) enantiomer of terazosin to bind toadrenergic receptors of the alpha 1 subtype was reported. In addition,in WO 92/16213, combinations of 5a-reductase inhibitory compounds andalpha1-adrenergic receptor blockers (terazosin, doxazosin, prazosin,bunazosin, indoramin, alfuzosin) were disclosed. However, no informationas to the alpha 1d, alpha 1b, or alpha 1a subtype specificity of thesecompounds was provided as this data and its relevancy to the treatmentof BPH was not known. Current therapy for BPH uses existingnon-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer),Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer).These non-selective antagonists suffer from side effects related toantagonism of the alpha 1d and alpha 1b receptors in the peripheralvasculature, e.g., hypotension and syncope.

The relatively recent cloning of the human alpha 1a adrenergic receptor(ATCC CRL 11140) and the use of a screening assay utilizing the clonedhuman alpha 1a receptor has enabled identification of compounds whichspecifically interact with the human alpha 1a adrenergic receptor. Forfurther description, see WO 94/08040 and WO 94/10989. As disclosed inthe instant patent disclosure, a cloned human alpha 1a adrenergicreceptor and a method for identifying compounds which bind the humanalpha 1a receptor has made possible the identification of selectivehuman alpha 1a adrenergic receptor antagonists useful for treating BPH.

Several classes of compounds have been disclosed to be selective alpha1a adrenergic receptor antagonists useful for treating BPH. WO 94/22829discloses, for example, certain 4-(un)substitutedphenyl-1,4-dihydropyridine derivatives which are described as potent,selective alpha 1a antagonists with weak calcium channel antagonisticactivity and which are further described to be anticipated as useful fortreating BPH. WO 94/22829 also discloses (see pages 30-35) a broadcollection of oxo-substituted, 6-membered heterocycle and carbocyclederivatives which generally embraces certain dihydropyridinones. Asanother example, WO 96/14846, WO 97/17969 and WO 97/42956 each disclosecertain dihydropyrimidine derivatives (e.g., certain1,2,3,6-tetrahydro-2-oxo-pyrimidine derivatives) which are selectiveantagonists for the human alpha 1a receptor and useful for treatment ofBPH, impotency, cardiac arrhythmia, and other diseases where antagonismof the alpha 1a receptor may be useful. As still another example, WO96/40135 discloses, inter alia, certain phenylpiperidinyl alkylsaccharin derivatives and their use as selective alpha 1a antagonists.

The instant patent disclosure discloses novel dihydropyridinone andpyrrolinone compounds which selectively bind to the human alpha 1areceptor. These compounds are further tested for binding to other humanalpha 1 receptor subtypes, as well as counterscreened against othertypes of receptors (e.g., alpha 2), thus defining the specificity of thecompounds of the present invention for the human alpha 1a adrenergicreceptor.

It is an object of the present invention to identify compounds whichbind to the alpha 1a adrenergic receptor. It is a further object of theinvention to identify compounds which act as antagonists of the alpha 1aadrenergic receptor. It is another object of the invention to identifyalpha 1a adrenergic receptor antagonist compounds which are usefulagents for treating BPH in animals, preferably mammals, especiallyhumans. Still another object of the invention is to identify alpha 1aadrenergic receptor antagonists which are useful for relaxing lowerurinary tract tissue in animals, preferably mammals, especially humans.

The compounds of the present invention are alpha 1a adrenergic receptorantagonists. Thus, the compounds of the present invention are useful fortreating BPH in mammals. Additionally, it has been found that the alpha1a adrenergic receptor antagonists of the present invention are alsouseful for relaxing lower urinary tract tissue in mammals.

SUMMARY OF THE INVENTION

The present invention provides dihydropyridinone and pyrrolinonecompounds for the treatment of urinary obstruction caused by benignprostatic hyperplasia (BPH). The compounds antagonize the human alpha 1aadrenergic receptor at nanomolar and subnanomolar concentrations whiletypically exhibiting at least about ten fold lower affinity for thealpha 1d and alpha 1b human adrenergic receptors and many otherG-protein coupled receptors. This invention has the advantage overnon-selective alpha 1 adrenoceptor antagonists of reduced side effectsrelated to peripheral adrenergic blockade. Such side effects includehypotension, syncope, lethargy, etc.

More particularly, the present invention is a compound of formula (I):

wherein

Y is CH or N;

X is CR⁴R⁵, when Y is N;

X is NR⁶, when Y is CH;

R¹ is phenyl, mono- or poly-substituted phenyl, naphthyl, mono- orpoly-substituted naphthyl, heterocyclic, or mono- or poly-substitutedheterocyclic; wherein the heterocyclic is selected from the groupconsisting of pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl andquinazolinyl; each of the substituents on the substituted phenyl orsubstituted naphthyl is independently selected from halo, nitro, cyano,hydroxy, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy, halogenated C₁-C₆alkyl, halogenated C₃-C₈ cycloalkyl, halogenated C₁-C₆ alkoxy,(CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂,NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); andeach of the substitutents on the substituted heterocyclic isindependently selected from halo, cyano, nitro, N(R^(c))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂,(CH₂)₀₋₄SO₂R^(c), phenyl, C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a), C₃-C₈ cycloalkyl, andhalogenated C₃-C₈ cycloalkyl;

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,tetrazole, isooxadiazole, phenyl, mono- or poly-substituted phenyl,naphthyl, mono- or poly-substituted naphthyl, heterocyclic, or mono- orpoly-substituted heterocyclic; wherein the heterocyclic is selected fromthe group consisting of pyridyl, thienyl and furanyl; each of thesubstituents on the substituted phenyl or substituted naphthyl isindependently selected from halo, cyano, nitro, hydroxy, C₁-C₆ alkoxy,halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₆ alkyl, halogenated C₁-C₆alkyl, C₃-C₈ cycloalkyl, and halogenated C₃-C₈ cycloalkyl; and each ofthe substituents on the substituted heterocyclic is independentlyselected from halo, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), phenyl C₁-C₆alkyl, halogenatedC₁-C₆ alkyl, C₁-C₆ alkoxy, halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a),C₃-C₈ cycloalkyl, and halogenated C₃-C₈ cycloalkyl; each R³ is asubstituent connected to a ring atom other than CR¹R² or Y and isindependently C₁-C₄ alkyl;

R⁴ and R⁵ are each independently selected from hydrogen, C₁-C₆ alkyl,and C₃-C₈ cycloalkyl;

R⁶ is hydrogen or C₁-C₄ alkyl;

R⁷ is phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, nitro, cyano, hydroxy, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkyl, halogenated C₃-C₈ cycloalkyl,halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and(CH₂)₀₋₄SO₂R^(c);

R⁸ is hydrogen, C₁-C₆ alkyl, (CH₂)₀₋₄CO₂R^(c), or (CH₂)₀₋₄C(═O)R^(c);

R⁹ is hydrogen, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkyl, halogenated C₃-C₈ cycloalkyl,halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), orC(═O)N(R^(c))₂;

R^(a) is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl;

R^(b) is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl;

R^(c) and R^(d) are each independently selected from hydrogen, C₁-C₆alkyl, C₃-C₈ cycloalkyl and (CH₂)₁₋₄CF₃;

m is an integer of from 0 to 2;

n is an integer of from 1 to 4, when X is NR⁶;

n is an integer of from 0 to 3, when X is CR⁴R⁵;

o is an integer equal to 0 or 1; and

p and q are each integers of from 0 to 2, wherein the sum of p+q is lessthan or equal to 3;

or a pharmaceutically acceptable salt thereof.

The present invention also includes pharmaceutical compositions, methodsof preparing pharmaceutical compositions, and methods of treatment.

These and other embodiments, aspects and features of the presentinvention are either further described in or will be apparent from theensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes dihydropyridinone and pyrrolinonecompounds of Formula (I) above. These compounds and theirpharmaceutically acceptable salts are useful as selective alpha 1aantagonists.

In a first embodiment, the present invention is a compound of Formula(I), wherein R¹ is phenyl, mono- or di-substituted phenyl, naphthyl,mono- or di-substituted naphthyl, heterocyclic, or mono- ordi-substituted heterocyclic;

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,tetrazole, isooxadiazole, phenyl, mono- or di-substituted phenyl,naphthyl, mono- or di-substituted naphthyl, heterocyclic, or mono- ordi-substituted heterocyclic;

R⁷ is selected from phenyl, or mono- or di-substituted phenyl;

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

In a second embodiment, the present invention is a compound of Formula(I), wherein R¹ is phenyl, mono- or di-substituted phenyl, pyridyl, ormono-or di-substituted pyridyl; wherein each of the substituents on thesubstituted phenyl is independently selected from halo, cyano, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₁-C₄alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and(CH₂)₀₋₄SO₂R^(c); and each of the substituents on the substitutedpyridyl is independently selected from halo, cyano, N(R^(c))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂,(CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy,halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a);

R² is hydrogen, cyano, hydroxy, C₁-C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,phenyl, mono- or di-substituted phenyl, pyridyl, or mono- ordi-substituted pyridyl; wherein each of the substituents on thesubstituted phenyl is independently selected from halo, cyano, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₁-C₄alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); and eachof the substituents on the substituted pyridyl is independently selectedfrom halo, C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c);

R⁷ is phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄alkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c),C(═O)N(R^(c))₂, SO₂N(R^(c))₂, and SO₂R^(c);

R^(a) is hydrogen, C₁-C₄ alkyl, or halogenated C₁-C₄ alkyl;

R^(b) is hydrogen, C₁-C₄ alkyl, or halogenated C₁-C₄ alkyl;

R^(c) and R^(d) are each independently selected from hydrogen, C₁-C₄alkyl and (CH₂)₁₋₂CF₃;

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

In a third embodiment, the present invention is a compound of Formula(I), wherein R¹ is phenyl, or mono- or di-substituted phenyl, pyridyl,or mono- or di-substituted pyridyl; wherein each of the substituents onthe substituted phenyl is independently selected from halo, cyano,hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenatedC₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and(CH₂)₀₋₄SO₂R^(c); and each of the substituents on the substitutedpyridyl is independently selected from halo, cyano, N(R^(c))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂,(CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy,halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a);

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), orC(═O)N(R^(c))₂;

R⁴ and R⁵ are either both hydrogen, or one of R⁴ and R⁵ is hydrogen andthe other is hydrogen, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;

R⁷ is phenyl, or mono- or di-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b),(CH₂)₀₋₄CF₃, OCF₃, N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂,NR^(c)SO₂R^(d), CO₂R^(c), C(═O)N(R^(c))₂, SO₂N(R^(c))₂, and SO₂R^(c);

R^(b) is C₁-C₄ alkyl or CF₃;

and all other variables are as originally defined above;

or a pharmaceutically acceptable salt thereof.

Other embodiments of the present invention include a compound of Formula(I), wherein

n is an integer of from 2 to 4, when X is NR⁶;

n is an integer of from 1 to 3, when X is CR⁴R⁵;

o is an integer equal to 0 or 1, provided that when Y is N, o is zero;and

all other variables are as originally defined above, or as defined abovein any one of the first, second, and third embodiments;

or a pharmaceutically acceptable salt thereof.

In a first class of the invention is a compound of Formula (II):

wherein

A is CR¹⁰ or N;

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, nitro, hydroxy, C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c);

R⁸ is hydrogen, C₁-C₄ alkyl, (CH₂)₀₋₄CO₂R^(c), or (CH₂)₀₋₄C(═O)R^(c);

R⁹ is hydrogen, halo, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy,(CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂;

R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c);

R¹² is hydrogen, halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁ -C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c);

R^(a) is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl;

R^(b) is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl;

R^(c) and R^(d) are each independently selected from hydrogen, C₁-C₆alkyl, C₃-C₈ cycloalkyl and (CH₂)₁₋₄CF₃;

n is an integer of from 0 to 3; and

r and s are independently integers of from 0 to 2;

or a pharmaceutically acceptable salt thereof.

In one aspect, the compound of Formula (II) is a (+) enantiomer or apharmaceutically acceptable salt thereof. In another aspect, thecompound of Formula (II) is a (−) enantiomer or a pharmaceuticallyacceptable salt thereof.

In a sub-class of the first class is a compound of Formula (II), wherein

R² is hydrogen, cyano, hydroxy, C₁-C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, hydroxy, C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂, N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), SO₂N(R^(c))₂,and SO₂R^(c);

R⁸ is hydrogen, C₁-C₄ alkyl, CO₂R^(c), or C(═O)R^(c);

R⁹ is hydrogen, halo, cyano, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy,(CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂;

R¹⁰ is hydrogen, halo, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c), C(═O)N(R^(c))₂,SO₂N(R^(c))₂, or SO₂R^(c);

R¹² is hydrogen, halo, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c), C(═O)N(R^(c))₂,SO₂N(R^(c))₂, or SO₂R^(c);

R^(a) is hydrogen, C₁-C₄ alkyl, or halogenated C₁-C₄ alkyl;

R^(b) is hydrogen, C₁-C₄ alkyl, or halogenated C₁-C₄ alkyl;

R^(c) and R^(d) are each independently selected from hydrogen and C₁-C₄alkyl;

n is an integer of from 1 to 3;

and all other variables are as originally defined above for the firstclass;

or a pharmaceutically acceptable salt thereof.

In an aspect of the preceding sub-class, R² is hydrogen, cyano, hydroxy,C₁-C₄ alkoxy, CO₂R^(c), or C(═O)N(R^(c))₂;

and all other variables are as defined in the sub-class;

or a pharmaceutically acceptable salt thereof.

In another sub-class of the first class is a compound of Formula (IIa):

wherein

A is CR¹⁰ or N;

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromfluoro, cyano, hydroxy, C₁-C₄ alkyl, (CH₂)₀₋₃CF₃, OCF₃, and(CH₂)₁₋₃OCF₃;

R⁸ is hydrogen or C₁-C₄ alkyl;

R⁹ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, (CH₂)₀₋₃CF₃, OCF₃,(CH₂)₁₋₃OCF₃, CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂;

each R¹⁰ is independently hydrogen, fluoro, cyano, hydroxy, C₁-C₄ alkyl,(CH₂)₀₋₃CF₃, OCF₃, or (CH₂)₁₋₃OCF₃;

each R^(c) is independently hydrogen, C₁-C₄ alkyl, or (CH₂)₁₋₄CF₃; and

r is an integer of from 0 to 2;

or a pharmaceutically acceptable salt thereof.

In one aspect, the compound of Formula (IIa) is a (+) enantiomer or apharmaceutically acceptable salt thereof. In another aspect, thecompound of Formula (IIa) is a (−) enantiomer or a pharmaceuticallyacceptable salt thereof.

Exemplifying the invention is a compound selected from the groupconsisting of:

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide;

4-(S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide;

4-(S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-4-cyano-piperdine-1-yl]-propyl}amide;

4-(S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-4-cyano-piperidine-1-yl]-propyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-4-cyano-piperidine-1-yl]-propyl}amide; and

pharmaceutically acceptable salts thereof.

Another example of the invention is a compound selected from the groupconsisting of:

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide, whichhas the formula:

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide, whichhas the formula:

and pharmaceutically acceptable salts thereof.

Still another example of the invention is4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide, whichhas the formula:

or a pharmaceutically acceptable salt thereof.

In still another sub-class of the first class is a compound of Formula(IIb):

wherein

A is CR¹⁰ or N;

R² is hydrogen, cyano, hydroxy, or methoxy;

R⁸ is hydrogen or methyl;

R⁹ is hydrogen or methyl;

each R¹⁰ is independently selected hydrogen, fluoro, cyano, hydroxy,methyl, methoxy, CF₃, or OCF₃; and

provided that when R² is hydrogen and A is CR¹⁰ wherein R¹⁰ is hydrogen,the other R¹⁰ is neither fluoro nor CF₃;

or a pharmaceutically acceptable salt thereof.

In one aspect, the compound of Formula (IIb) is a (+) enantiomer or apharmaceutically acceptable salt thereof. In another aspect, thecompound of Formula (IIb) is a (−) enantiomer or a pharmaceuticallyacceptable salt thereof.

In a second class of the invention is a compound of Formula (III):

wherein

A is CR¹⁰ or N;

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, nitro, hydroxy, C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c);

R⁸ is hydrogen, C₁-C₄ alkyl, (CH₂)₀₋₄CO₂R^(c), or (CH₂)₀₋₄C(═O)R^(c);

R⁹ is hydrogen, halo, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy,(CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂;

R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c);

R¹² is hydrogen, halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c);

R^(a) is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl;

R^(b) is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl;

R^(c) and R^(d) are each independently selected from hydrogen, C₁-C₆alkyl, C₃-C₈ cycloalkyl and (CH₂)₁₋₄CF₃;

n is an integer of from 1 to 4; and

r and s are independently integers of from 0 to 2;

or a pharmaceutically acceptable salt thereof.

In one aspect, the compound of Formula (III) is a (+) enantiomer or apharmaceutically acceptable salt thereof. In another aspect, thecompound of Formula (III) is a (−) enantiomer or a pharmaceuticallyacceptable salt thereof. In yet another aspect, in the compound ofFormula (III), n is an integer of from 2 to 4, and all other variablesare as originally defined for the second class; or a pharmaceuticallyacceptable salt thereof.

In a sub-class of the second class is a compound of Formula (III),wherein

R² is hydrogen, cyano, hydroxy, C₁-C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, hydroxy, C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂, N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), SO₂N(R^(c))₂,and SO₂R^(c);

R⁸ is hydrogen, C₁-C₄ alkyl, CO₂R^(c), or C(═O)R^(c);

R⁹ is hydrogen, halo, cyano, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy,(CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂;

R¹⁰ is hydrogen, halo, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c), C(═O)N(R^(c))₂,SO₂N(R^(c))₂, or SO₂R^(c);

R¹² is hydrogen, halo, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c), C(═O)N(R^(c))₂,SO₂N(R^(c))₂, or SO₂R^(c);

R^(a) is hydrogen, C₁-C₄ alkyl, or halogenated C₁-C₄ alkyl;

R^(b) is hydrogen, C₁-C₄ alkyl, or halogenated C₁-C₄ alkyl;

R^(c) and R^(d) are each independently selected from hydrogen and C₁-C₄alkyl;

and all other variables are as originally defined above for the secondclass;

or a pharmaceutically acceptable salt thereof.

In one aspect of the preceding sub-class, R² is hydrogen, cyano,hydroxy, C₁-C₄ alkoxy, CO₂R^(c), or C(═O)N(R^(c))₂;

and all other variables are as defined in the sub-class;

or a pharmaceutically acceptable salt thereof.

In a further aspect of the preceding sub-class, n is an integer of from2 to 4; and all other variables are as defined in the sub-class; or apharmaceutically acceptable salt thereof.

Further exemplifying the invention is a compound selected from the groupconsisting of:

4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide;

4-(S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide;

4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide; and

pharmaceutically acceptable salts thereof.

The present invention also includes a pharmaceutical compositioncomprising a therapeutically effective amount of any of the compoundsdescribed above and a pharmaceutically acceptable carrier. In oneembodiment is a pharmaceutical composition made by combining any of thecompounds described above and a pharmaceutically acceptable carrier. Thepresent invention further includes a process for making a pharmaceuticalcomposition comprising combining any of the compounds described aboveand a pharmaceutically acceptable carrier.

The present invention further includes a pharmaceutical composition asdescribed in the preceding paragraph further comprising atherapeutically effective amount of a testosterone 5-alpha reductaseinhibitor. In one embodiment, the testosterone 5-alpha reductaseinhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., athree component combination comprising any of the compounds describedabove combined with both a type 1 testosterone 5-alpha reductaseinhibitor and a type 2 testosterone 5-alpha reductase inhibitor), or adual type 1 and type 2 testosterone 5-alpha reductase inhibitor. Inanother embodiment, the testosterone 5-alpha reductase inhibitor is atype 2 testosterone 5-alpha reductase inhibitor. The testosterone5-alpha reductase inhibitor is suitably finasteride.

The present invention also includes a method of treating benignprostatic hyperplasia in a subject in need thereof which comprisesadministering to the subject a therapeutically effective amount of anyof the compounds (or any of the compositions) described above. In oneembodiment of the method of treating BPH, the compound (or composition)does not cause a fall in blood pressure at dosages effective toalleviate BPH. In another embodiment of the method of treating BPH, thecompound is administered in combination with a testosterone 5-alphareductase inhibitor. A suitable testosterone 5-alpha reductase inhibitorfor use in the method is finasteride.

The present invention also includes a method of inhibiting contractionof prostate tissue or relaxing lower urinary tract tissue in a subjectin need thereof which comprises administering to the subject atherapeutically effective amount of any of the compounds (or any of thecompositions) described above. In one embodiment of the method ofinhibiting contraction of prostate tissue or relaxing lower urinarytract tissue, the compound (or composition) additionally does not causea fall in blood pressure at dosages effective to inhibit contraction ofprostate tissue. In another embodiment, the compound is administered incombination with a testosterone 5-alpha reductase inhibitor; thetestosterone 5-alpha reductase inhibitor is suitably finasteride.

The present invention also includes a method of treating a disease whichis susceptible to treatment by antagonism of the alpha 1a receptor whichcomprises administering to a subject in need thereof an amount of any ofthe compounds described above effective to treat the disease. Diseaseswhich are susceptible to treatment by antagonism of the alpha 1areceptor include, but are not limited to, BPH, high intraocularpressure, high cholesterol, impotency, sympathetically mediated pain,migraine (see K. A. Vatz, Headache, Vol. 37, 107-108 (1997)) and cardiacarrhythmia.

The present invention also includes the use of any of the compoundsdescribed above in the preparation of a medicament for: a) treatingbenign prostatic hyperplasia; b) relaxing lower urinary tract tissue; orc) inhibiting contraction of prostate tissue; in a subject in needthereof.

The present invention further includes the use of any of the alpha 1aantagonist compounds described above and a 5-alpha reductase inhibitorfor the manufacture of a medicament for: a) treating benign prostatichyperplasia; b) relaxing lower urinary tract tissue; or c) inhibitingcontraction of prostate tissue which comprises an effective amount ofthe alpha 1a antagonist compound and an effective amount of 5-alphareductase inhibitor, together or separately.

As used herein, the term “C₁-C₆ alkyl” means linear or branched chainalkyl groups having from 1 to 6 carbon atoms and includes all of thehexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- andt-butyl, n- and isopropyl, ethyl and methyl. “C₁-C₄ alkyl” means n-,iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “C₁-C₆ alkoxy” means an —O-alkyl group wherein alkyl is C₁ toC₆ alkyl. “C₁-C₄ alkoxy” has an analogous meaning; i.e., it is an alkoxygroup selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, and sec-butoxy.

The term “C₃-C₈ cycloalkyl” means a cyclic ring of an alkane havingthree to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). “C₃-C₆ cycloalkyl”refers to a cyclic ring selected from cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term “halo” (which may alternatively be referred to as “halogen”)refers to fluoro, chloro, bromo, and iodo (alternatively fluorine,chlorine, bromine and iodine).

The term “halogenated C₁-C₆ alkyl” (which may altenatively be referredto as “C₁-C₆ haloalkyl”) means a C₁ to C₆ linear or branched alkyl groupas defined above with one or more halogen substituents. The term“halogenated C₁-C₄ alkyl” has an analogous meaning. Representativeexamples of suitable haloalkyls include the series (CH₂)₀₋₄CF₃ (i.e.,trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.),tribromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl2-bromoethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl,and perfluorohexyl.

The term “halogenated C₃-C₈ cycloalkyl” (which may altenatively bereferred to as “C₃-C₈ halocycloalkyl”) means a cycloalkyl group asdefined above with one or more halogen substituents. “Halogenated C₃-C₆cycloalkyl” has an analogous meaning. Representative examples ofsuitable halocycloalkyls include all isomers of fluorocyclohexyl (i.e.,1-, 2-, 3-, and 4-fluorocyclohexyl), difluorocyclohexyl (e.g.,2,4-difluorocyclohexyl, 3,4-difluorocyclohexyl, etc.), bromocyclohexyl,fluorocyclopentyl, and so forth.

The term “halogenated C₁-C₆ alkoxy” (which may altenatively be referredto as “C₁-C₆ haloalkoxy”) means a C₁-C₆ alkoxy group as defined abovewherein the alkyl moiety has one or more halogen substituents.“Halogenated C₁-C₄ alkoxy” has an analogous meaning. Representativeexamples include the series O(CH₂)₀₋₄CF₃ (i.e., trifluoromethoxy,2,2,2-trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), chloromethoxy,chloroethoxy, 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.

The term “heterocyclic” (which may alternatively be referred to as“heterocycle”) refers to pyridyl, pyrazinyl, thienyl, thiazolyl, furanyland quinazolyl. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.

The term “thienyl,” as used herein, refers to the group

The term “aryl” refers to phenyl, substituted phenyl, naphthyl, andsubstituted naphthyl.

The term “heteroaryl” refers to heterocyclic or substitutedheterocyclic.

The term “substituted” includes mono- and poly-substitution by a namedsubstituent to the extent such single and multiple substitution ischemically allowed.

The term “poly-substituted” refers herein to multiple degrees ofsubstitution by a named substituent or substituents. For example, theterm “poly-substituted phenyl” denotes di-, tri-, tetra- andpenta-substitution by a named substituent or a combination of namedsubstituents (e.g., “di-substituted phenyl wherein each substituent isindependently selected from fluoro, rnethoxy and cyano” represents suchmoieties as 2,4-difluorophenyl, 3,4-difluorophenyl,2-methoxy-4-fluorophenyl, 2-fluoro-4-cyanophenyl,2-cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, etc.)

It is understood that the definition of a substituent (e.g.,(CH₂)₀₋₄CO₂R^(c)) or variable (e.g., R^(c)) at a particular location ina molecule is independent of its definitions at other locations in thatmolecule. Thus, for example, when R¹ is mono-substituted phenyl whereinthe substituent is (CH₂)₀₋₄CO₂R^(c)=CO₂H, and R⁷ is alsomono-substituted phenyl wherein the substituent is (CH₂)₀₋₄CO₂R^(c), itis understood that the substituent on the phenyl in R⁷ can be any one ofCO₂H, CO₂Me, CO₂Et, CO₂Pr, CH₂CO₂H, CH₂CO₂Me, CH₂CO₂Et, CH₂CO₂Pr,(CH₂)₂CO₂H, etc. As another example, the moiety

wherein R³ is C₁-C₄ alkyl, m=2, o=1, and p=1, represents moieties suchas

It is also understood that the definition of a substituent or variableat a particular location in a molecule is independent of the definitionof another occurrence of the same substituent or variable at the samelocation. Thus, C(═O)N(R^(c))₂ represents groups such as —C(═O)NH₂,—C(═O)NHMe, —C(═O)NHEt, —C(═O)NMe₂, —C(═O)N(Me)Et, etc.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by the methods set forth below and, whenviewed in the light of this disclosure, by techniques known in the art.Where multiple substituent moieties are disclosed or claimed, thesubstituted compound can be independently substituted by one or more ofthe disclosed or claimed substituent moieties, singly or plurally.

Other embodiments for the variables and substituents set forth inFormula (I) include the following:

R¹ is phenyl, mono- or poly-substituted phenyl, pyridyl, or mono- orpoly-substituted pyridyl; or is phenyl, mono- or di-substituted phenyl,pyridyl, or mono- or di-substituted pyridyl. In still other embodiments,R¹ is phenyl, or mono- or di-substituted phenyl; or is pyridyl, or mono-or di-substituted pyridyl.

When R¹ is substituted phenyl, each of the substituents is independentlyselected from halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR_(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); or is selected from halo,cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and(CH₂)₀₋₄SO₂R^(c). In still other embodiments, each of the substituentsis independently selected from halo, nitro, cyano, hydroxy, C₁-C₄ alkyl,C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenatedC₃-C₆ cycloalkyl, halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a); or isselected from fluoro, cyano, hydroxy, C₁-C₄ alkyl, (CH₂)₀₋₃CF₃, OCF₃,and (CH₂)₁₋₃OCF₃.

When R¹ is substituted pyridyl, each of the substituents isindependently selected from halo, cyano, nitro, N(R^(c))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂,(CH₂)₀₋₄SO₂R^(c), phenyl, C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), C₃-C₆ cycloalkyl, andhalogenated C₃-C₆ cycloalkyl; or is independently selected from halo,cyano, N(R^(c))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl, halogenated C₁-C₄alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a). Instill other embodiments, each of the substituents is independentlyselected from halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a); or is selectedfrom fluoro, cyano, hydroxy, C₁-C₄ alkyl, (CH₂)₀₋₃CF₃, OCF₃, and(CH₂)₁₋₃OCF₃.

In yet another embodiment, R¹ is

wherein A is C-R¹⁰ or N; R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl,halogenated C₃-C₆ cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a),N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c); and r is an integer of from 0to 2.

R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,tetrazole, isooxadiazole, phenyl, mono- or poly-substituted phenyl,pyridyl, or mono- or poly-substituted pyridyl; or is hydrogen, cyano,hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂, tetrazole,isooxadiazole, phenyl, mono- or di-substituted phenyl, or mono- ordi-substituted pyridyl; or is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy,CO₂R^(c), C(═O)N(R^(c))₂, tetrazole, isooxadiazole, or phenyl. In stillother embodiments, R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy,CO₂R^(c), C(═O)N(R^(c))₂, tetrazole, or isooxadiazole; or is hydrogen,cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), or C(═O)N(R^(c))₂.

When R² is substituted phenyl, each of the substituents is independentlyselected from halo, cyano, nitro, hydroxy, C₁-C₄ alkoxy, halogenatedC₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl,halogenated C₁-C₄ alkyl, C₃-C₆ cycloalkyl, and halogenated C₃-C₆cycloalkyl; or is independently selected from halo, cyano, hydroxy,C₁-C₄ alkoxy, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a),(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl, and halogenatedC₁-C₄ alkyl; or is independently selected from fluoro, cyano, hydroxy,C₁-C₄ alkyl, (CH₂)₀₋₃CF₃, OCF₃, and (CH₂)₁₋₃OCF₃.

When R² is substituted pyridyl, each of the substituents isindependently selected from halo, (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), phenyl,C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄alkoxy, (CH₂)₁₋₄OR^(a), C₃-C₆ cycloalkyl, and halogenated C₃-C₆cycloalkyl; or is independently selected from halo, (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₄alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkoxy,and (CH₂)₁₋₄OR^(a).

R³ is methyl, ethyl, n-propyl, or isopropyl; or is methyl or ethyl.

R⁴ and R⁵ are each independently selected from hydrogen and C₁-C₄ alkyl.In other embodiments, R⁴ and R⁵ are both hydrogen; or one of R⁴ and R⁵is hydrogen and the other is hydrogen or C₁-C₄ alkyl. In still anotherembodiment, R⁴ and R⁵ together with the carbon atom to which they areattached form methylene (—CH₂—) units or alkylidene units of formula(—CR′H—) wherein R′ is C₁-C₄ alkyl or, in cases where there are at leasttwo CR⁴R⁵'s (e.g., when n=2), mixtures of the foregoing units.

R⁶ is hydrogen, methyl, or ethyl; or is hydrogen.

R⁷ is phenyl, or mono- or di-substituted phenyl; or is mono- ordi-substituted phenyl.

When R⁷ is substituted phenyl, each of the substituents is independentlyselected from halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR_(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); or is independently selectedfrom halo, cyano, hydroxy, C₁-C₄ alkyl C₁-C₄ alkoxy, halogenated C₁-C₄alkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); or is independently selectedfrom halo, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄alkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c),C(═O)N(R^(c))₂, SO₂N(R^(c))₂, and SO₂R^(c). In other embodiments, eachof the substituents is independently selected from halo, nitro, cyano,hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄alkyl, halogenated C₃-C₆ cycloalkyl, halogenated C₁-C₄ alkoxy, and(CH₂)₁₋₄OR^(b); or is selected from fluoro, cyano, hydroxy, C₁-C₄ alkyl,(CH₂)₀₋₃CF₃, OCF₃, and (CH₂)₁₋₃OCF₃.

In still another embodiment, R⁷ is

wherein R¹² is hydrogen, halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c); and s is an integer of from 0to 2.

R⁸ is hydrogen, C₁-C₄ alkyl, (CH₂)₀₋₄CO₂R^(c), or (CH₂)₀₋₄C(═O)R^(c); oris hydrogen, C₁-C₄ alkyl, CO₂R^(c), or C(═O)R^(c).

R⁹ is hydrogen, halo, cyano, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), orC(═O)N(R^(c))₂; or is hydrogen, halo, cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy,halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b),CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂. In still another embodiment, R⁹is hydrogen, halo, cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, (CH₂)₀₋₃CF₃, OCF₃,(CH₂)₁₋₃OCF₃, CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂.

Each of R^(a) and R^(b) is independently hydrogen, C₁-C₄ alkyl, orhalogenated C₁-C₄ alkyl; or is C₁-C₄ alkyl or halogenated C₁-C₄ alkyl;or is C₁-C₄ alkyl or (CH₂)₀₋₃CF₃. In another embodiment, each of R^(a)and R^(b) is independently hydrogen, methyl, ethyl, CF₃, or CH₂CF₃.

R^(c)and R^(d) are each independently selected from hydrogen, C₁-C₄alkyl, C₃-C₆ cycloalkyl and (CH₂)₁₋₄CF₃; or are each independentlyselected from hydrogen, C₁-C₄ alkyl, and (CH₂)₁₋₄CF₃. In still anotherembodiment, R^(c)and R^(d) are each independently selected fromhydrogen, methyl, ethyl, CF₃, and CH₂CF₃.

Halo is fluoro or bromo; or is fluoro.

m is 0 or 1; or is 0.

n is an integer of from 2 to 4, when X is NR⁶; or n is 3, when X is NR⁶.

n is an integer of from 1 to 3, when X is CR⁴R⁵; or n is 2, when X isCR⁴R⁵.

o is an integer equal to 1; or is an integer equal to 0 or 1, providedthat when Y is N, o is zero.

p and q are each integers of from 0 to 2, wherein the sum of p+q is 2;i.e., p=1 and q=1, or p=0 and q=2, or p=2 and q=0.

Representative compounds of the present invention exhibit highselectivity for the human alpha 1a adrenergic receptor. One implicationof this selectivity is that these compounds display selectivity forlowering intraurethral pressure without substantially affectingdiastolic blood pressure.

Representative compounds of this invention display submicromolaraffinity for the human alpha 1a adrenergic receptor subtype whiletypically displaying at least about ten-fold lower affinity for thehuman alpha 1d and alpha 1b adrenergic receptor subtypes, and many otherG-protein coupled human receptors. Particular representative compoundsof this invention exhibit nanomolar and subnanomolar affinity for thehuman alpha 1a adrenergic receptor subtype while displaying at leastabout 30 fold lower affinity for the human alpha 1d and alpha 1badrenergic receptor subtypes, and many other G-protein coupled humanreceptors (e.g., serotonin, dopamine, alpha 2 adrenergic, betaadrenergic or muscarinic receptors). Still other representativecompounds of this invention exhibit nanomolar and subnanomolar affinityfor the human alpha 1a adrenergic receptor subtype while displaying atleast about 100 fold lower affinity for the human alpha 1d and alpha 1badrenergic receptor subtypes, and many other G-protein coupled humanreceptors (e.g., serotonin, dopamine, alpha 2 adrenergic, betaadrenergic or muscarinic receptors).

These compounds are administered in dosages effective to antagonize thealpha 1a receptor where such treatment is needed; e.g., treatment ofBPH. For use in medicine, the salts of the compounds of this inventionrefer to non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of the compounds according to theinvention or in the prepartion of their pharmaceutically acceptablesalts. Suitable pharmaceutically acceptable salts of the compounds ofthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound according to the inventionwith a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g. quatemary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, n-methylglucamine ammoniumsalt, oleate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate.

Compounds of this invention are used to reduce the acute symptoms ofBPH. Thus, compounds of this invention may be used alone or incombination with more long-term anti-BPH therapeutics, such astestosterone 5-a reductase inhibitors, including PROSCAR® (finasteride).Aside from their utility as anti-BPH agents, these compounds may be usedto induce highly tissue-specific, localized alpha 1a adrenergic receptorblockade whenever this is desired. Effects of this blockade includereduction of intra-ocular pressure, control of cardiac arrhythmias, andpossibly a host of alpha 1a receptor mediated central nervous systemevents.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in Design of Prodrugs, ed. H. Bundgaard,Elsevier, 1985. Metabolites of these compounds include active speciesproduced upon introduction of compounds of this invention into thebiological milieu.

Where the compounds according to the invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundsaccording to the invention possess two or more chiral centers, they mayadditionally exist as diastereoisomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Furthermore, some of the crystalline forms forcompounds of the present invention may exist as polymorphs and as suchare intended to be included in the present invention. In addition, someof the compounds of the present invention may form solvates with water(i.e., hydrates) or common organic solvents. Such solvates are alsoencompassed within the scope of this invention.

The term “selective alpha 1a adrenergic receptor antagonist,” as usedherein, refers to an alpha 1a antagonist compound which exhibitsselectivity (e.g., at least about ten fold selective) for the humanalpha 1a adrenergic receptor as compared to the human alpha 1b, alpha1d, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.

The term “lower urinary tract tissue,” as used herein, refers to andincludes, but is not limited to, prostatic smooth muscle, the prostaticcapsule, the urethra and the bladder neck.

The term “subject,” as used herein refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated.

The present invention includes pharmaceutical compositions comprisingone or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the compositions may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

As used herein, the term “composition” encompasses a product comprisingthe specified ingredients in the specified amounts, as well as anyproduct which results, directly or indirectly, from combination of thespecified ingredients in the specified amounts.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

The specificity of binding of compounds showing affinity for the alpha1a receptor is shown by comparing affinity to membranes obtained fromtransfected cell lines that express the alpha 1a receptor and membranesfrom cell lines or tissues known to express other types of alpha (e.g.,alpha 1d, alpha 1b) or beta adrenergic receptors. Expression of thecloned human alpha 1 d, alpha 1b, and alpha 1a receptors and comparisonof their binding properties with known selective antagonists provides arational way for selection of compounds and discovery of new compoundswith predictable pharmacological activities. Antagonism by thesecompounds of the human alpha 1a adrenergic receptor subtype may befunctionally demonstrated in anesthetized animals. These compounds maybe used to increase urine flow without exhibiting hypotensive effects.

The ability of compounds of the present invention to specifically bindto the alpha 1a receptor makes them useful for the treatment of BPH. Thespecificity of binding of compounds showing affinity for the alpha 1areceptor is compared against the binding affinities to other types ofalpha or beta adrenergic receptors. The human alpha adrenergic receptorof the 1a subtype was recently identified, cloned and expressed asdescribed in PCT International Application Publication Nos. WO94/08040,published Apr. 14, 1994 and WO 94/21660, published Sep. 29, 1994. Thecloned human alpha 1a receptor, when expressed in mammalian cell lines,is used to discover ligands that bind to the receptor and alter itsfunction. Expression of the cloned human alpha 1d, alpha 1b, and alpha1a receptors and comparison of their binding properties with knownselective antagonists provides a rational way for selection of compoundsand discovery of new compounds with predictable pharmacologicalactivities.

Compounds of this invention exhibiting human alpha 1a adrenergicreceptor antagonism may further be defined by counterscreening. This isaccomplished according to methods known in the art using other receptorsresponsible for mediating diverse biological functions. [See e.g. PCTInternational Application Publication No. WO94/10989, published May 26,1994; U.S. Pat. No. 5,403,847, issued Apr. 4, 1995]. Compounds which areboth selective amongst the various human alpha1 adrenergic receptorsubtypes and which have low affinity for other receptors, such as thealpha 2 adrenergic receptors, the β-adrenergic receptors, the muscarinicreceptors, the serotonin receptors, and others are particularlypreferred. The absence of these non-specific activities may be confirmedby using cloned and expressed receptors in an analogous fashion to themethod disclosed herein for identifying compounds which have highaffinity for the various human alpha1 adrenergic receptors. Furthermore,functional biological tests are used to confirm the effects ofidentified compounds as alpha 1a adrenergic receptor antagonists.

The present invention also has the objective of providing suitabletopical, oral, systemic and parenteral pharmaceutical formulations foruse in the novel methods of treatment of the present invention. Thecompositions containing compounds of this invention as the activeingredient for use in the specific antagonism of human alpha 1aadrenergic receptors can be administered in a wide variety oftherapeutic dosage forms in conventional vehicles for systemicadministration. For example, the compounds can be administered in suchoral dosage forms as tablets, capsules (each including timed release andsustained release formulations), pills, powders, granules, elixirs,tinctures, solutions, suspensions, syrups and emulsions, or byinjection. Likewise, they may also be administered in intravenous (bothbolus and infusion), intraperitoneal, subcutaneous, topical with orwithout occlusion, or intramuscular form, all using forms well known tothose of ordinary skill in the pharmaceutical arts. An effective butnon-toxic amount of the compound desired can be employed as an alpha 1aantagonistic agent.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using those forms of transdermal skin patches well known to those ofordinary skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.Optimal precision in achieving concentration of drug within the rangethat yields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methylcellulose and the like. Other dispersing agents which may beemployed include glycerin and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever specific blockade of the human alpha 1a adrenergic receptor isrequired.

The daily dosage of the products may be varied over a wide range; e.g.,from about 0.01 to about 1000 mg per adult human per day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0 and 100 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably, from about 1 mg to about 100 mg of activeingredient. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weightper day. Preferably, the range is from about 0.001 to about 10 mg/kg ofbody weight per day, and especially from about 0.001 mg/kg to about 7mg/kg of body weight per day. The compounds may be administered on aregimen of 1 to 4 times per day.

Compounds of this patent disclosure may be used alone at appropriatedosages defined by routine testing in order to obtain optimal antagonismof the human alpha 1a adrenergic receptor while minimizing any potentialtoxicity. In addition, co-administration or sequential administration ofother agents which alleviate the effects of BPH is desirable. Thus, inone embodiment, this invention is administration of compounds of thisinvention and a human testosterone 5-a reductase inhibitor. Includedwith this embodiment are inhibitors of 5-alpha reductase isoenzyme 2.Many such compounds are now well known in the art and include suchcompounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; seeU.S. Pat. Nos. 4,377,584 and 4,760,071, for example). In addition toPROSCAR®, which is principally active in prostatic tissue due to itsselectivity for human 5-a reductase isozyme 2, combinations of compoundswhich are specifically active in inhibiting testosterone 5-alphareductase isozyme 1 and compounds which act as dual inhibitors of bothisozymes 1 and 2, are useful in combination with compounds of thisinvention. Compounds that are active as 5a-reductase inhibitors havebeen described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038,;WO93/23048; WO93/23041; WO93/23040; WO93/23039; WO93/23376; WO93/23419,EP 0572165; WO93/23051.

The dosages of the alpha 1a adrenergic receptor and testosterone 5-alphareductase inhibitors are adjusted when combined to achieve desiredeffects. As those skilled in the art will appreciate, dosages of the5-alpha reductase inhibitor and the alpha 1a adrenergic receptorantagonist may be independently optimized and combined to achieve asynergistic result wherein the pathology is reduced more than it wouldbe if either agent were used alone. In accordance with the method of thepresent invention, the individual components of the combination can beadministered separately at different times during the course of therapyor concurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly.

Thus, in one embodiment of the present invention, a method of treatingBPH is provided which comprises administering to a subject in need oftreatment any of the compounds of the present invention in combinationwith finasteride effective to treat BPH. The dosage of finasterideadministered to the subject is from about 0.01 mg per subject per day toabout 50 mg per subject per day in combination with an alpha 1aantagonist. In one aspect, the dosage of finasteride in the combinationis from about 0.2 mg per subject per day to about 10 mg per subject perday, and, in another aspect, from about 1 to about 7 mg per subject today (e.g., about 5 mg per subject per day).

For the treatment of benign prostatic hyperplasia, compounds of thisinvention exhibiting alpha 1a adrenergic receptor blockade can becombined with a therapeutically effective amount of a 5a-reductase 2inhibitor, such as finasteride, in addition to a 5a-reductase 1inhibitor, such as 4,7β-dimethyl-4-aza-5a-cholestan-3-one, in a singleoral, systemic, or parenteral pharmaceutical dosage formulation.Alternatively, a combined therapy can be employed wherein the alpha 1aadrenergic receptor antagonist and the 5a-reductase 1 or 2 inhibitor areadministered in separate oral, systemic, or parenteral dosageformulations. See, e.g., U.S. Pat. No. 4,377,584 and U.S. Pat. No.4,760,071 which describe dosages and formulations for 5a-reductaseinhibitors.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

ACN=acetonitrile

AcOH=acetic acid

Bn=benzyl

Boc or BOC=t-butyloxycarbonyl

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

EDC=1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride

Et=ethyl

Et₃N=triethylamine

EtOAc=ethyl acetate

HOAt=1-hydroxy-7-azabenzotriazole

HPLC=high performance liquid chromatography

LDA=lithium diisopropylamide

Me=methyl

MeOH=methanol

MP=melting point

MS=mass spectrometry

n-BuLi=n-butyllithium

NMR=nuclear magnetic resonance

Pr=propyl

Tf=triflic or triflate

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

The compounds of the present invention can be prepared readily accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

Many of the compounds claimed within this invention can be assembled viaSchemes I and II shown below. Scheme I describes the preparation ofamines (4, 6, 8, 12) suitable for the preparation of many of thecompounds of the present invention. In Scheme I, part a,1-Boc-4-piperidone or a substituted analog (1) can be treated with LDAfollowed by N-triflic amide to provide the corresponding triflate 2.Palladium catalyzed coupling with an aryl or heteroaryl organozincateR¹ZnX, followed by hydrogenation of the resulting alkene and nitrogendeprotection with HCl(g) affords a substituted piperidine hydrochlorideof type 3. Alkylation with 3-bromo-1-Boc-propylamine in the presence oftriethylamine followed by deprotection with HCl(g) affords amine 4.Alkylation with other monoprotected amines of general formulaBr(CR⁴R⁵)_(n)NHBoc, followed by deprotection allows for the preparationof a diverse range of amines of type 4.

As shown in Scheme I, part b, the piperidone 1 can be reacted withGrignard reagents R¹MgX to provide tertiary alcohols of type 5, whichcan be converted to amines of type 6. Alkylation with othermonoprotected amines of general formula Br(CR⁴R⁵)_(n)NHBoc, followed bydeprotection allows for the preparation of a diverse range of amines oftype 6.

As shown in Scheme I, part c, aryl- and heteroaryl-acetonitriles can betreated with a base such as NaH or cesium carbonate and withbis-(2-chloroethyl)-tert-butoxycarbonylamine to afford the piperidinederivatives of type 7. Deprotection and alkylation as described beforegives access to amines of type 8. Alkylation with other monoprotectedamines of general formula Br(CR⁴R⁵)_(n)NHBoc, followed by deprotectionallows for the preparation of a diverse range of amines of type 8.

As shown in Scheme I, part d, triflate 10 can readily be prepared from1,4-cyclohexanedione monoethylene ketal (9) using LDA and triflic amide.Palladium catalyzed coupling with an aryl or heteroaryl organozincateR¹ZnX, followed by hydrogenation of the resulting alkene and hydrolysisof the ketal with 1N HCl in dioxane provides ketone 11. Reductiveamination of the previous ketone with mono-Boc ethylenediamine followedby deprotection affords cyclohexylamines of type 12. Reductive aminationwith other monoprotected diamines of general formula H₂N(CR⁴R⁵)_(n)NHBocfollowed by deprotection allows for the preparation of a diverse rangeof amines of type 12.

Scheme II describes the preparation of dihydropyridinone derivatives 14and 15 and their coupling to amines 4, 6, 8, 12 as needed for thepreparation of many of the compounds of the present invention.Dihydropyridinones 13 can be prepared in racemic form byheterocyclization of arylaldehydes R⁷CHO and b-ketoesters with Meldrum'sacid, according to Seoane's and Svetlik's procedures (J. HeterocyclicChem., 1996, 33, 103; J. Chem. Soc. Perkin Trans. 1, 1996, 947-951; J.Chem. Soc. Perkin Trans. 1, 1990, 1315-1318). Hydrogenolysis of theresulting benzyl ester or hydrolysis of alkyl ester provides ofdihydropyridinone carboxylic acid derivative 14. Standard amine couplingusing EDC/HOAt and the amines 4, 6, 8, and 12 described in Scheme Iafford compounds of type 16 as racemates. Chiral preparative HPLCseparation provides each enantiomer separately.

Further according to Scheme II, amide 13 can also be alkylated oracylated (R⁸X, R⁸COX, R⁸OCOX) using standard procedures prior to esterhydrogenolysis or hydrolysis, to provide carboxylic acids of type 15.Standard amine coupling using EDC/HOAt and the amines 4, 6, 8, and 12described in Scheme I afford compounds of type 17 as racemates. Chiralpreparative HPLC separation provides each enantiomer separately.Alternatively, esters of type 13 can be resolved by chiral preparativeHPLC to allow for the preparation of compounds of type 16 and 17 assingle enantiomers directly.

Substituted pyrrolinones (5-membered ring analogs of intermediates 14and 15) can be prepared from arylglyoxal and enamines according toCaballerro's procedure as described in (Tetrahedron, 1994, 50,7849-7856) and coupled to amines 4, 6, 8, and 12 as needed for thepreparation of many of the compounds of the present invention.

Scheme III below outlines the specific procedures set forth in Examples10-13 for preparing the dihydropyridinone precursors employed inExamples 14-33.

Scheme IV below outlines the specific procedures set forth in Examples1-9 for preparing the amines employed in Examples 14-33.

The following Examples further describe and illustrate the invention andits practice and are not to be construed as limiting the scope or spiritof the invention.

EXAMPLE 1 3- [4-(2-Pyridyl)-piperidin-1-yl]propylamine

Step A. 1-(3-Aminopropyl)-4-[2-pyridyl]pyridinium bromide hydrobromide

A solution of 2,4′-dipyridyl (25 g, 160 mmol) and 3-bromopropylaminehydrobromide (35 g, 160 mmol) in DMF (60 mL) was heated at 90-95° C. for10 h. After cooling to room temperature, anhydrous ether (500 mL) wasadded to the mixture. The resulting white solid was filtered, washedwith ether and dried.

¹H NMR (300 MHz, DMSO) δ 2.35-2.44 (m, 2 H), 3.08-3.13 (m, 2 H),4.76-4.81 (m, 2 H), 7.58 (dd, J=4.8 Hz, J=7.5 Hz, 1 H), 8.03 (dt, J=1.8Hz, J=7.8 Hz, 1 H), 8.32 (d, J=7.8 Hz, 1 H), 8.77-8.81 (m, 3 H), 9.12(d, J=6.3 Hz, 2 H). Anal. Calcd. for C₁₃H₁₆N₃Br.HBr.0.5 H₂O: C, 40.65;H, 4.72; N, 10.94. Found: C, 40.83; H, 4.37; N, 11.05.

Step B. 3-(3′,6′-Dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine

To a solution of 1-(3-aminopropyl)-4-[2-pyridyl]pyridinium bromidehydrobromide (6 g, 16 mmol) in MeOH (150 mL) at 0° C. was added NaBH₄ (2g, 53 mmol) in small portions over a period of 2 h. The reaction mixturewas stirred overnight at room temperature and the solvent wasevaporated. The residue was suspended in ether (200 mL) and treated with50% NaOH solution (100 mL). The ether layer was separated and theaqueous layer was extracted with ether (2×50 mL). The combined etherextracts were dried over potassium carbonate and the solvent was removedto give 3-(3′,6′-dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine as anoil. It was immediately used in the next step without purification.

Step C. 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine

To a solution of3-(3′,6′-dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propylamine (3.48 gcrude, 15.9 mmol) in MeOH (40 mL), was added 1.0 g of palladiumhydroxide catalyst. The suspension was hydrogenated under 120 psi for 10h after which the reaction mixture was filtered through a pad of Celiteand the solvent was removed. The residue was purified by columnchromatography over silica gel (30 g) [Note: If a large excess of silicagel is used the recovery of the product will be very low] usingmethylene chloridemethanol/2M ammonia in MeOH (90:8:4 to 90:40:40) aseluent. The product was obtained as a pale yellow oil.

¹H NMR δ (CD₃OD) 1.50-1.99 (m, 10 H), 2.02-2.06 (m, 2 H), 2.37-2.75 (m,3 H), 3.02-3.06 (br m, 2 H), 7.05-7.09 (m, 4 H), 7.16 (dt, J=0.9Hz,J=8.7 Hz, 1 H), 8.48 (dd, J=0.9 Hz, J=4.2 Hz, 1 H).

EXAMPLE 2 3-[4-(4-Fluorophenyl)piperidin-1-yl]propylamine

Step A. 4-(4-Fluorophenyl)piperidine hydrochloride

To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridinehydrochloride (10 g) in methanol (200 mL) was added 10% palladium oncharcoal (0.5 g) and the mixture was hydrogenated at 50 psi for 3 h. Thecatalyst was removed by filtration and solvent was evaporated to leavethe product as a white powder, which was used in the next step withoutany purification.

MP 181-182° C.

¹H NMR (CDCl₃): δ 1.95-2.03 (br d, 2H), 2.14-2.29 (m, 2H), 2.70-2.80 (m,1H), 2.91-3.07 (br q, 2H), 3.60-3.64 (br d, 2H), 6.96-7.03 (m, 2H),7.19-7.22 (m, 2H), 9.60 (br s, 1H), 9.71 (br s, 1H).

Step B. 3-[4-(4-Fluorophenyl)piperidin-1-yl] propylphthalimide

A mixture of 4-(4-fluorophenyl)piperidine hydrochloride (5.08 g, 23.2mmol), 3-bromopropylphthalimide (6.22 g, 23.2 mmol), and potassiumcarbonate (15 g) in DMF (100 mL) was stirred and heated at 95-100° C.for 12 h. About 80% of the solvent was evaporated at reduced pressure,the residue was diluted with ethyl acetate (200 mL) and washed withbrine (3×100 mL) and dried (Na₂SO₄). Solvent was evaporated and theresidue was purified by column chromatography on silica gel using 1/1hexane-ethyl acetate to 100% ethyl acetate as eluent. This product wascrystallized from isopropanol to give a white crystalline solid; m.p.80-81° C. This material was used in the next step. Concentration of themother liquor and cooling gave the second crop.

¹H NMR (CDCl₃): δ 1.43-1.52 (m, 2H), 1.67-1.75 (m, 2H), 1.80-1.96 (m,4H), 2.33-2.46 (m, 3H), 2.94-2.99 (br d, 2H), 3.78 (t, J=7 Hz, 2H),6.90-7.04 (m, 4H), 7.70-7.74 (m, 2H), 7.84-7.87 (m, 2H).

Step C. 3-[4-(4-Fluorophenyl)piperidin-1-yl]propylamine

To a solution of 3-[4-(4-fluorophenyl)piperidin-1-yl] propylphthalimide(4.5 g, 12.3 mmol) in methanol (200 mL) was added 4 ml of hydrazine andthe mixture was stirred and refluxed for 8 h. It was cooled, and thewhite solid was filtered and washed with methanol (20 mL). Solvent wasevaporated, and the residue was dried under vacuum for 4 h. Chloroform(50 mL) was added to this material, it was stirred for 1 h and filtered.The white solid was washed with more chloroform (20 mL), and the solventwas evaporated from the combined filtrates to leave the crude product asan oil. It was purified by column chromatography on silica gel usingdichloromethane/methanol/2M ammonia in methanol (10/3/1) as the eluent.

¹H NMR (CDCl₃): δ 1.60-1.83 (m, 6H), 1.96-2.07 (m, 4H), 2.40-2.55 (m,3H), 2.70-2.85 (br t, 2H), 3.03-3.07 (br d, 2H), 6.93-7.00 (m, 2H),7.14-7.20 (m, 2H).

EXAMPLE 3 3-[4-(2-Cyano-4-fluorophenyl)-piperidin-1-yl]propylamine,hydrochloride salt

Step A. 4-(2-Cyano-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of 2-bromo-5-fluorobenzonitrile (8.1 g, 40.5 mmole) in THF(50 mL) was added rapidly to a solution of n-BuLi (20 mL, 2.5M, 50mmole) in THF at −78° C. and the resulting solution is stirred for 5minutes. To this solution was added ZnCl₂, (0.5 M in THF, 89 mL, mmoles)and the solution was warmed to 0° C. Palladiumtetrakistriphenylphosphine (1.5 g, 1.3 mmole) was added followed bytrifluoromethanesulfonic acid[1-tert-butoxycarbonyl-(1,2,3,6-tetra-hydropyridin-4-yl)] ester fromExample 7, step A below (9 g, 27.16 mmole). The reaction was heated to40° C. for 30 minutes and then cooled to room temperature and pouredinto saturated aqueous sodium bicarbonate (1 L). The mixture wasextracted with ethyl acetate (3×300 mL) and the combined organicextracts were dried over anhydrous magnesium sulfate, filtered andconcentrated at reduced pressure. The residue was chromatographed onsilica gel eluting with 15% to 30% ethyl acetate/hexanes to give theproduct.

¹H NMR (CDCl₃): δ 7.4-7.25 (m, 3H), 5.95 (br s, 1H), 4.09 (br s, 2H),3.65-3.60 (m, 2H), 2.50 (m, 2H), 1.50 (s, 9H).

Step B. 4-(2-Cyano-4-fluorophenyl)-piperidine-1-carboxylic acidtert-butyl ester

4-(2-Cyano-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (7.89 g, 26.1 mmol) and 10% Palladium on carbon (3.95g) were combined in absolute ethanol (270 ml) containing acetic acid(0.79 ml) and the mixture hydrogenated at 60 psi for 2.5 hrs. Thecatalyst was removed by filtration through super cel and the filtrateconcentrated to dryness in vacuo to give a crude oil. Flashchromatography on silica gel (10% to 15% ethyl acetate in hexane) gavethe product as a colorless oil.

¹H NMR (CDCl₃): δ 7.35-7.25 (m, 3H), 4.30-4.11 (br d, 2H), 3.15-3.06 (m,1H), 2.91-2.82 (t, 2H), 1.87-1.82 (br d, 2H), 1.68-1.62 (m, 2H), 1.49(s, 9H).

Step C. 4-(2-cyano-4-fluorophenyl) piperidine hydrochloride

An ethyl acetate solution (56 ml) of4-(2-Cyano-4-fluorophenyl)-piperidine-1-carboxylic acid tert-butyl ester(5.64 g, 18.5mmol) was cooled to 0° C. and hydrogen chloride gas wasbubbled through the solution until saturated (10 min). The solution wasstirred in the cold (20 min) and then concentrated in vacuo to give theproduct as a white solid.

¹H NMR (CD₃OD): δ 7.61-7.53 (m, 2H), 7.53-7.43 (m, 1H), 3.60-3.50 (m,2H), 3.40-3.16 (m, 3H), 2.18-1.94 (m, 4H).

Step D. 3-[4-(2-Cyano-4-fluorophenyl)-piperidin-1-yl]propylamine,hydrochloride

A suspension of 4-(2-cyano-4-fluorophenyl) piperidine hydrochloride (2.5g, 10.4 mmol), 3-bromo-1-tert-butoxycarbonylpropylamine (3.22 g, 13.5mmol) and triethylamine (3.76 ml, 27 mmol) in DMF (12 ml) was stirred atroom temperature for 16 hours. The reaction mixture was diluted withethyl acetate (200 mL)and washed with saturated bicarbonate solution,water×2 and brine. Drying and solvent evaporation gave after flashchromatography (silica gel, ethyl acetate) 3.1 g of2-[1-(3-tert-butoxycarbonylaminopropyl)piperidin-4-yl]-4-fluorobenzonitrile. This material was dissolved inEtOAc (200 mL), cooled to 0° C. and HCl gas was bubbled into thesolution for 15 minutes. The reaction mixture was concentrated atreduced pressure to give the the title compound.

¹H NMR (CD₃OD): δ 7.65-7.50 (m, 2H), 7.5-7.43 (m, 1H), 3.75-3.65 (m,2H), 3.40-3.1 (m, 3H), 2.25-2.1 (m, 4H).

EXAMPLE 4 3-[4-(4-Fluorophenyl)-4-cyano-piperidin-1-yl]propylamine,dihydrochloride salt

Step A. Bis-(2-chloro-ethyl)-tert-butoxycarbonylamine

To a solution of bis(2-chloroethyl)amine hydrochloride (10 g, 56.66mmol) in 210 ml 2.5:1 dioxane:H₂O was added triethylamine (7.88 mL,56.66 mmol). This solution was cooled to 0° C. under argon, and Bocanhydride (14.96, 68.58 mmol) was added dropwise. This was stirred for45 min, poured onto saturated sodium bicarbonate, and extracted withethyl acetate. The combined organic layers were washed with saturatedsodium chloride, dried with magnesium sulfate, and concentrated in vacuoto give the product.

¹H NMR δ_(H) (CDCl₃) 3.70-3.55 (m, 8H), 1.47 (s, 9H).

Step B. 4-(4-Fluorophenyl)-4-cyano-tert-butoxycarbonylpiperidine

To a solution of bis-(2-chloro-ethyl)-tert-butoxycarbonylamine (3.0 g,12.39 mmol) in 75 mL of DMF was added 4-fluorobenzylacetonitrile (1.515g, 11.27 mmol). This solution was cooled to 0° C., and a 60% dispersionof sodium hydride was added portion wise (1.17 g, 29.25 mmol). Thesolution was stirred for 20 min, warmed to room temperature, then heatedto 80° C. for 24 h. It was poured onto water, and extracted with ethylacetate. The combined organic layers were washed with saturated sodiumchloride, dried with magnesium sulfate, and concentrated in vacuo. Thecrude material was passed through silica (25% ethyl acetate, hexane) togive the product.

¹H NMR δ_(H) (CDCl₃) 7.50-7.40 (m, 2H), 7.15-7.05 (m, 2H), 4.40-4.20 (brm, 2H), 3.30-3.10 (br m, 2H), 2.15-2.05 (m, 2H), 2.00-1.85 (m, 2H), 1.49(s, 9H).

Step C. 4-(4-Fluorophenyl)-4-cyano-piperidine hydrochloride

A solution of 4-(4-fluorophenyl)-4-cyano-tert-butoxycarbonylpiperidine(840 mg, 2.74 mmol) in 50 mL ethyl acetate was cooled to 0° C. Hydrogenchloride gas was bubbled through the solution for 2 min. It was stirredfor 10 min and then concentrated in vacuo to give the product.

¹H NMR δ_(H) (CD₃OD) 7.65-7.55 (M, 2H), 7.30-7.20 (m, 2H), 3.68-3.60 (m,2H), 3.45-3.00 (m, 2H), 2.50-2.25 (m, 4H).

Step D.1-(3-tert-Butoxycarbonylamino-propyl)-4-(4-fluorophenyl)-4-cyano-piperidine

The free base of 4-(4-fluorophenyl)-4-cyano piperidine hydrochloride wasprepared by pouring the salt onto saturated sodium carbonate extractingwith ethyl acetate, drying the organic layers with sodium sulfate,filtering, and concentrating in vacuo. To a solution of4-(4-fluorophenyl)-piperidine-4-carbonitrile (300 mg, 1.578 mmol) in 4mL of DMF was added 3-bromopropyl-tert-butoxycarbonylamine (387 mg,1.626 mmol) and triethylamine (225 mL, 1.623 mmol) under argon. Thesolution was stirred for 2 h at 60° C., poured onto saturated sodiumbicarbonate, and extracted with ethyl acetate. The combined organiclayers were washed with saturated sodium chloride, dried with magnesiumsulfate, and concentrated in vacuo . The crude material was passedthrough silica (5% methanol, dichloromethane) to give the product.

¹H NMR δ_(H) (CDCl₃) 7.50-7.45 (m, 2H), 7.15-7.05 (m, 2H), 5.40 (br s,1H), 3.23-3.21 (m, 2H), 3.06-3.02 (m, 2H), 2.55-2.46 (m, 4H), 2.10-2.06(m, 4H), 1.70-1.64 (m, 2H).

Step E. 3-[4-(4-Fluorophenyl)-4-cyano-piperidin-1-yl]propylamine,dihydrochloride salt

A solution of1-(3-tert-butoxycarbonylamino-propyl)-4-(4-fluorophenyl)-4-cyanopiperidine (480 mg, 1.33 mmol) in 50 mL ethyl acetate was cooled to 0°C. Hydrogen chloride gas was bubbled through the solution for 2 min, andit was stirred for 20 min and then concentrated in vacuo to give thetitle product.

¹H NMR δ_(H) (CD₃OD) 7.66-7.61 (m, 2H), 7.26-7.20 (m, 2H), 3.85-8.81 (m,2H), 3.45-3.25 (m, 4H), 3.10 (t, 2H, J=7.6 Hz), 2.60-2.52 (m, 4H),2.28-2.15 (m, 2H).

EXAMPLE 53-[4-(2-Cyano-4-fluorophenyl)-4-cyano-piperidin-1-yl]propylamine,hydrochloride salt

Step A. 2-Cyano-4-fluorophenylacetonitrile

A solution of 1.0 g (7.2 mmol) 2,5-difluorobenzonitrile, 1.2 ml (8.4mmol) tert-butyl cyanoacetate, and 3.5 g (10.7 mmol) cesium carbonate in30 ml DMSO was heated to 100° C. for 2 hours. The reaction was cooled toroom temperature, diluted with 600 ml ether, washed with 300 ml 10%KHSO₄, 300 ml dilute brine, and 300 ml brine. The ether layer was driedover MgSO₄, filtered, and concentrated to give 1.6 g of an oil (TLCRf=0.34 (20% EtOAc:hexanes)). This oil was dissolved in 100 ml1,2-dichloroethane and 0.5 ml trifluoroacetic acid was slowly added. Thereaction was heated to reflux for 4 hours, cooled, diluted with 200 mlether, washed with 100 ml saturated aqueous sodium bicarbonate solution,100 ml brine, then dried over MgSO4, filtered, and concentrated invacuo. Purification by flash chromatography (4×12 cm silica gel, lineargradient 20-50% EtOAc:hexanes) afforded the title compound.

¹H NMR (300 MHz, CDCl₃) δ 7.64 (m, 1H); 7.41 (m, 2H); 3.95 (s, 2H).

Step B. 4-Cyano-4-(2-cyano-4-fluorophenyl)-piperidine-1-carboxylic acidtert butyl ester.

To a solution of 0.098 g (0.61 mmol) 2-cyano-4-fluorophenylacetonitrileand 0.17 g (0.07 mmol) N-Boc-di-(2-chloroethyl)amine in 3 ml DMSO wasadded 0.69 g (2.1 mmol) cesium carbonate. The reaction was stirred 24 hat room temperature, then diluted with 100 ml ethyl acetate, washed with100 ml aqueous 10% KHSO₄ solution, 100 ml saturated sodium bicarbonatesolution, 100 ml brine; then dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (3×12 cmsilica gel, linear gradient 0-4% acetone/CH₂Cl₂) afforded the titlecompound. TLC Rf=0.25 (30% EtOAc:hexanes).

H NMR (400 MHz, CDCl₃) δ 7.65 (m, 1H); 7.50 (m, 1H); 7.37 (m, 1H); 4.37(br m, 2H); 3.25 (br m, 2H); 2.30 (m, 4H); 1.50 (s, 9H).

Step C.1-(3-N-Bocaminopropyl)-4-cyano-4-(2-cyano-4-fluorophenyl)-piperidine.

To a 0° C. solution of 0.53 g (1.63 mmol)4-cyano-4-(2-cyano-4-fluorophenyl)-piperidine-1-carboxylic acid tertbutyl ester in 10 ml ethyl acetate was bubbled through HCl gas for 5minutes. The heterogeneous reaction mixture was stirred 5 more minutesat 0° C., then diluted with 70 ml EtOAc and extracted 2×75 ml H₂O. Thecombined aqueous extracts were brought to pH 11 with 3 ml 50% aqueousNaOH and extracted 3×50 ml ethyl acetate, adding solid NaCl to eachextraction. The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to give 0.33 g of an oil that was dissolved in10 ml DMF. To this was added 0.3 ml (2.1 mmol) triethylamine and 0.38 g(1.6 mmol) N-Boc-3-bromopropylamine. The reaction mixture was stirred 24hours at room temperature, then diluted with 200 ml ethyl acetate,washed with 100 ml saturated aqueous sodium bicarbonate solution, 100 mlwater, and 100 ml brine; then dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (3×12 cmsilica gel, linear gradient 2-5% MeOH/1% NH₄OH/CH₂Cl₂) afforded thetitle compound.

¹H NMR (400 MHz, CDCl₃) δ 7.60 (dd, 1H, J=9.16 and 5.13 Hz); 7.51 (dd,1H, J=7.69 and 2.93 Hz); 7.35 (m, 1H); 5.10 (br s, 1H); 3.20 (m, 2H);3.08 (d, 2H, J=12.5 Hz); 2.54 (m, 4H); 2.40 (d, 2H, J=12.5 Hz); 2.25(dt, 2H, J=2.54 and 11.9 Hz); 1.70 (quint, 2H, J=6.45 Hz); 1.43 (s, 9H).

Step D.3-[4-(2-Cyano-4-fluorophenyl)-4-cyano-piperidin-1-yl]propylamine,dihydrochloride salt

To a 0° C. solution of 0.38 g (1 mmol) mmol)1-(3-N-Bocaminopropyl)-4-cyano-4-(2-cyano-4-fluorophenyl)-piperidine in5 ml ethyl acetate was bubbled through HCl gas for 5 minutes. Theheterogeneous reaction mixture was stirred 5 more minutes at 0° C., thenconcentrated in vacuo to give the title product.

¹H NMR (300 MHz, CD₃OD) δ 7.82 (dd, 1H, J=8.06 and 2.93 Hz); 7.75 (dd,1H, J=8.79 and 4.88 Hz); 7.60 (m, 1H); 3.95 (d, 2H, J=13.0 Hz); 3.41 (m,4H); 3.10 (t, 2H, J=7.57 Hz); 2.90 (m, 2H); 2.63 (br t, 2H, J=14.7 Hz);2.23 (m, 2H).

EXAMPLE 6 3-[4-(2,4-difluorophenyl)-4-cyano-piperidin-1-yl]propylamine,dihydrochloride salt

The title product was prepared by procedures similar those describedabove for Example 4 except substituting 2,4-difluorophenyl acetonitrilein Step B.

¹H NMR δ_(H) (CD₃OD) 7.66-7.55 (m, 2H), 7.21-7.05 (m, 2H), 3.90-3.85 (m,2H), 3.55-3.25 (m, 4H), 3.15-3.05 (m, 2H), 2.70-2.55 (m, 4H), 2.30-2.015(m, 2H).

EXAMPLE 7 3-[4-(2-Cyanophenyl)-piperidin-1-yl]propylamine, hydrochloridesalt

Step A. Trifluoromethanesulfonicacid[1-tert-butoxycarbonyl-(1,2,3,6-tetrahydro-pyridin-4-yl)]ester

To a solution of diisopropylamine (13.4 ml, 0.096 mol) intetrahydrofuran (400 ml), cooled to −78° C. was added n-butyllithium(2.5 M in hexanes, 38.4 ml, 0.096 mol) followed by addition of1-tert-butoxycarbonyl-4-piperidone (16 g, 0.080 mol) in tetrahydrofuran(200 ml). After stirring for 10 minutes, a solution ofN-phenyltrifluoromethane sulfonimide (31.4 g, 0.088 mol) intetrahydrofuran (100 ml) was added. The reaction mixture was stirred for15 minutes at −78° C., allowed to warm to room temperature and quenchedwith saturated bicarbonate solution. The reaction was diluted with etherand washed with 15% potassium hydrogen sulfate, saturated bicarbonatesolution, 1N sodium hydroxide×4, water×2 and brine. Drying and solventevaporation gave a solid; flash chromatography (silica gel, hexane-ethylacetate, 95:5) gave trifluoromethanesulfonicacid[1-tert-butoxycarbonyl-(1,2,3,6-tetrahydropyridin-4-yl)]ester.

¹H NMR (CDCl₃) δ 1.48 (s, 9H), 2.44 (m, 2H), 3.63 (t, 2H, J=5.6 Hz),4.04 (d, 2H, J=2.6 Hz), 5.76 (bs, 1H)

Step B.2-[1-tertbutoxycarbonyl-(1,2,3,6-tetrahydropyridin-4-yl)]benzonitrile

To a suspension of trifluoromethanesulfonicacid[1-tert-butoxycarbonyl-(1,2,3,6-tetrahydropyridin-4-yl)]ester (10.5g, 0.032 mol) and tetrakis(triphenylphosphine) palladium(0) (1.8 g, 1.6mmol) in tetrahydrofuran (95 ml) was added iodo(2-cyanophenyl)zinc (0.5Min tetrahydrofuran, 94 ml, 0.047 mol) dropwise. The reaction mixture wasstirred at room temperature for 0.5 hours and quenched with saturatedbicarbonate solution. The mixture was diluted with ethyl acetate andwashed with water×2 and brine. Drying and solvent evaporation gave anoil; flash chromatography (silica gel, hexane-ethyl acetate, 92:8) gavethe title compound.

¹H NMR (CDCl₃) δ 1.50 (s, 9H), 2.53 (m, 2H), 3.67 (t, 2H, J=6.0 Hz),4.12 (d, 2H, J=3.2 Hz), 5.98 (m, 1H), 7.34 (m, 2H), 7.54 (bt, 1H, J=7.6Hz), 7.66 (bd, 1H, J=8 Hz).

Step C. 2-(1-tert-Butoxycarbonylpiperidin-4-yl)benzonitrile

To a solution of2-[(1-tert-butoxycarbonyl-(1,2,3,6-tetrahydropyridin-4-yl)]benzonitrile(5.3 g, 0.019 mol) and acetic acid (0.28 ml, 4.9 mmol) in ethanol (200ml), degassed with argon was added palladium on carbon. The reaction washydrogenated on a Parr apparatus at 50 psi for 15 hours. The mixture wasrecharged twice with acetic acid (0.14 ml, 0.28 ml) and palladium oncarbon (900 mg, 1.8 g), hydrogenated as above and filtered throughcelite. Solvent evaporation gave2-(1-tert-butoxycarbonylpiperidin-4-yl)benzonitrile.

¹H NMR (CDCl₃) δ 1.49 (s, 9H), 1.64 (m, 2H), 1.86 (bd, 2H, J=13.4 Hz),2.88 (bt, 2H, J=14 Hz), 3.14 (tt, 1H, J=12 Hz, J=4 Hz), 4.27 (bs, 2H),7.31 (m, 2H), 7.56 (bt, 1H, J=7.7 Hz), 7.63 (bd, 1H, J=7.7 Hz)

Step D. 2-(Piperidin-4-yl)benzonitrile hydrochloride

To a solution of 2-(1-tertbutoxycarbonylpiperidin-4-yl)benzonitrile (1.7g, 5.9 mmol) in ethyl acetate (˜50 ml), cooled to 0° C. was addedhydrogen chloride gas, bubbled vigorously for 5 minutes. The reactionmixture was stirred for 10 minutes at 0° C., purged with argon andconcentrated. Flushing with ethyl acetate×3 and concentration gave2-(piperidin-4-yl) benzonitrile hydrochloride.

¹H NMR (DMSO) δ 1.98 (m, 4H), 3.07 (m, 2H), 3.21 (tt, 1H, J=12 Hz, J=3.8Hz), 3.36 (m, 2H), 7.46 (m, 2H), 7.74 (bt, 1H, J=7.7 Hz), 7.83 (bd, 1H,J=7.0 Hz), 9.10 (bd, 2H).

Step E. 3-Bromo-1-tertbutoxycarbonylpropylamine

To a suspension of 3-bromopropylamine hydrobromide (5.0 g, 0.023 mol)and di-tert-butyl dicarbonate(5.0 g, 0.023 mol) in methylene chloride(125 ml), cooled to 0° C. was added triethylamine (3.2 ml, 0.023 mol).The reaction mixture was stirred for 3 hours at room temperature,diluted with methylene chloride and washed with water×2 and brine.Drying and solvent evaporation gave3-bromo-1-tert-butoxycarbonylpropylamine.

¹H NMR (CDCl₃) δ 1.46 (s, 9H), 2.05 (m, 2H), 3.28 (m, 2H), 3.43 (m, 2H),4.64 (bs, 1H).

Step F. 2-[1-(3-tert-Butoxycarbonylaminopropyl)piperidin-4-yl]benzonitrile

A suspension of 2-(piperidin-4-yl)benzonitrile hydrochloride (600 mg,2.7 mmol), 3-bromo-1-tert-butoxycarbonylpropylamine (0.67 g, 2.8 mmol)and triethylamine (0.77 ml, 5.5 mmol) in DMF (12 ml) was stirred at roomtemperature for 15 hours. The reaction mixture was diluted with ethylacetate and washed with saturated bicarbonate solution, water×2 andbrine. Drying and solvent evaporation gave an oil (0.86 g); flashchromatography (silica gel, ethyl acetate) gave2-[1-(3-tert-butoxycarbonylaminopropyl) piperidin-4-yl]benzonitrile.

¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.69 (m, 2H), 1.80 (bt, 2H,J=12 Hz), 1.89(m, 2H), 2.12 (bt, 2H, J=10.8 Hz), 2.47 (t, 2H, J=6.7 Hz), 2.97-3.08 (m,3H), 3.22 (m, 2H), 5.61 (bs, 1H), 7.29 (m, 1H), 7.39 (bd, 1H, J=7.9 Hz),7.54 (bt, 1H, J=7.7 Hz), 7.62 (bd, 1H, J=7.7 Hz).

Step G. 3-[4-(2-Cyanophenyl)-piperidin-1-yl]propylamine, hydrochloridesalt

To a solution of2-[1-(3-tert-butoxycarbonylamino-propyl)piperidin-4-yl]benzonitrile(0.73 g, 2.1 mmol) in ethyl acetate (100 ml), cooled to 0° C. was addedhydrogen chloride gas, bubbled vigorously for 5 minutes. The reactionmixture was stirred for 10 minutes at 0° C., purged with argon andconcentrated. Flushing with ethyl acetate×2 and concentration gave thetitle product.

¹H NMR (DMSO) δ 2.00 (m, 2H), 2.10 (m, 2H), 2.28 (m, 2H), 2.95 (m, 2H),3.18 (m, 4H), 3.56 (bd, 2H, J=1.7 Hz), 7.47 (m, 2H), 7.75 (bt, 1H, J=8Hz), 7.84 (bd, 1H, J=7.9 Hz), 8.14 (bs, 2H), 11.1 (bd, 1H).

EXAMPLE 8 3-[4-(2-Cyanophenyl)-4-cyano-piperidin-1-yl]propylamine,hydrochloride salt

This product was prepared by a procedure similar to Example 5 startingwith 2-fluorobenzonitrile.

¹H NMR δ_(H) (CDCl₃) 7.97-7.95 (d, 1H, J=7.1 Hz), 7.83-7.80 (t, 1H,J=7.1), 7.72-7.63 (m, 2H), 3.95-3.90 (d, 2H, J=15 Hz), 3.51-3.29 (m,4H), 3.12-3.07 (t, 2H, J=7.8), 2.93-2.88 (br m, 2H), 2.67-2.55 (m, 2H),2.22-2.01 (m, 2H).

EXAMPLE 9 trans-2-[4-(2-Amino-ethylamino)-cyclohexyl]-benzonitrilehydrochloride cis-2-[4-(2-Amino-ethylamino)-cyclohexyl]-benzonitrilehydrochloride

Step A. Trifluoromethanesulfonic acid 1,4-dioxa-spiro[4.5]dec-7-en-8-ylester

To a solution of diisopropylamine (7.6 mL, 54.3 mmol) in 200 mL THFcooled to −78° C. was added n-butyllithium (21.8 mL 2.5 M in hexane,54.3 mmol) under argon. The solution was stirred for 10 minutes, then asolution of 1,4-cyclohexanedione monoethylene ketal (8.5 g, 54.3 mmol)in 75 mL THF was added slowly. The solution was stirred for 10 min, thena solution of N-phenyltrifluoromethane sulfonamide (19.5 g, 54.3 mmol)in 150 mL THF was added slowly. The reaction solution was warmed tor.t., poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodiumchloride, dried with magnesium sulfate, and concentrated in vaccuo. Thecrude material was passed through silica (3% methanol, dichloromethane)to give the product as an oil.

¹H NMR δ_(H) (CDCl₃) 5.7-5.6 (m, 1H), 4.1-4.0 (m, 4H), 2.6-2.5 (m, 2H),2.5-2.4 (m, 2H), 1.9 (t, 2H, J 6.6).

Step B. 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile

To a solution of trifluoromethanesulfonic acid1,4-dioxa-spiro[4.5]dec-7-en-8-yl ester (12.5 g, 45.2 mmol) in THF (100mL) at room temperature was added a solution of iodozinc benzonitrile(100 mL of a 0.5 N solution in THF, 50 mmol) and palladiumtetrakistriphenylphophine (1 g, 0.8 mmol). The reaction was heated to80° C. for 1 hour. The reaction was cooled to room temperature andpoured into saturated sodium bicarbonate (1L), and extracted with ethylacetate. The combined organic layers were washed with saturated sodiumchloride, dried with magnesium sulfate, and concentrated in vacuo. Thecrude material was chromatographed over silica gel eluting with 25%ethylacetate/hexane to give the product as a pale yellow oil.

¹H NMR δ_(H) (CDCl₃) 7.7-7.6 (m, 1H), 7.52 (dt, 1H, J=2, 7 Hz), 7.4-7.26(m, 2H), 5.95-5.88 (m, 1H), 4.05-4.0 (m, 4H), 2.7-2.6 (m, 2H), 2.55-2.48(m, 2H), 1.95 (t, 2H, J=6.6 Hz).

Step C. 2-(1,4-Dioxaspiro[4.5]dec-8-yl)benzonitrile

To a suspension of 10% palladium on carbon (1.5 g) in ethyl acetate (200mL) at room temperature under argon was added a solutioin of2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (8.9 g, 36.7 mmol) inethyl acetate (50 mL). Hydrogen gas was then bubbled into the reactionmixture until all the starting material was consumed. The reaction wasfiltered through celite to remove the catalyst and the solutionconcentrated to give the product as a colorless oil.

¹H NMR δ_(H) (CDCl₃) 7.65-7.6 (m, 1H), 7.54 (dt, 1H, J=2, 7 Hz),7.46 (brd, 2H, J=7 Hz), 7.28 (dt, 1H, J=2, 7 Hz), 4.05-4.0 (m, 4H), 3.1-3.0 (m,1H), 2.0-1.7 (m, 8H)

Step D. 2-(4-Oxocyclohexyl)benzonitrile

To a stirring solution of 2-(1,4-dioxaspiro[4.5]dec-8-yl)benzonitrile(8.7 g, 35.7 mmol) in dioxane (200 mL) was added 1N HCl (200 mL) and thereaction heated to 80° C. for 2 hours. The reaction was cooled to roomtemperature and poured into water (1 L) the mixture was extracted withethyl acetate (3×250 mL). The combined organics were washed with brine(200 mL) and then dried over anhydrous magnesium sulfate, filtered andconcentrated at reduced pressure to give the product.

¹H NMR δ_(H) (CDCl₃) 7.65-7.6 (br d, 1H, J=7 Hz), 7.59 (br t, 1H, J=7Hz),7.40-7.30 (m, 2H), 3.5 (tt, 1H, J=3, 10 Hz), 2.7-2.5 (m, 4H),2.35-2.2 (m, 2H), 2.05-1.90 (m, 2H).

Step E. trans-2-[4-(2-Amino-ethylamino)-cyclohexyl]-benzonitrilehydrochloride and cis-2-[4-(2-Amino-ethylamino)-cyclohexyl]-benzonitrilehydrochloride

To a solution of 2-(4-oxocyclohexyl)benzonitrile (2.0 g, 10.0 mmol) andacetic acid (2.15 mL, 15.0 mmol) in 50 mL methanol was adddedN-tert-butoxycarbonyl-ethylenediamine (2.40 g, 15.0 mmol) under argon.The solution was stirred for 2 h, then sodium cyanoborohydride (14.8 mL1M in THF, 15.0 mmol) was added dropwise. The solution was poured ontosaturated sodium bicarbonate, and extracted with ethylacetate. Thecombined organic layers were washed with saturated sodium chloride,dried with magnesium sulfate, and concentrated in vaccuo. The crudematerial was passed through silica (10% methanol, ethylactate) to give3:1 trans:cis2-[4-(2-tertbutoxycarbonylamino-ethylamino)-cyclohexyl]-benzonitrile.

Thetrans-2-[4-(2-tertbutoxycarbonylamino-ethylamino)-cyclohexyl]-benzonitrilewas dissolved in 200 mL ethylacetate, and HCl gas was bubbled throughthe solution for 1 h. The solution was concentrated in vaccuo to givethe trans product.

¹H NMR δ_(H) (CD₃OD) 7.75-7.60 (m, 2H), 7.52-7.49 (d, 1H, J=7.8 Hz),7.42-7.39 (t, 1H, J=7.6 Hz), 3.38-3.36 (m, 4H), 3.07-3.03 (m, 1H),2.40-2.30 (m, 2H), 2.10-2.05 (m, 2H), 1.78-1.64 (m, 4H).

Thecis-2-[4-(2-tertbutoxycarbonylamino-ethylamino)-cyclohexyl]-benzonitrile(0.343 g, 1.57 mmol) was dissolved in 200 mL ethyl acetate, and HCl gaswas bubbled through the solution for 1 h. The solution was concentratedin vaccuo to give the cis product.

¹H NMR δ_(H) (CD₃OD) 7.82-7.80 (d, 1H, J-8.06 Hz), 7.79-7.63 (m, 2H),7.41-7.35 (t, 1H, J=7.3 Hz), 3.60-3.50 (br s, 1H), 3.45-3.40 (m, 3H),3.20-3.05 (m, 1H), 2.25-2.15 (m, 2H), 2.10-1.95 (m, 4H), 1.9-1.3 (m,2H).

EXAMPLE 104-(R,S)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid

Benzyl acetoacetate (7.69 g, 40 mmol), dimethyl dioxane dione (Meldrum'sacid, 5.77 g, 40 mmol), 3,4-difluorobenzaldehyde (5.68 g, 40 mmol) andammonium acetate (3.24 g, 42 mmol) were combined in acetic acid (40 ml)and the reaction mixture was refluxed for 2.5 hrs. After cooling to roomtemperature the reaction mixture was poured on ice and the resultingmixture was diluted with water, extracted with diethyl ether and ethylacetate. The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 30% ethyl acetate in hexane to 50% and thensilica gel, 50% diethyl ether in hexane to 100% diethyl ether) toprovide after recrystalization from ethyl acetate/hexane:4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-benzylacetate as a white crystalline solid. A second crop was obtained fromthe mother liquor.

¹H NMR (CDCl₃): δ 8.35 (br s, 1H), 7.40-6.80 (m, 8H), 5.10 (AB q, 2H),4.25 (d, 1H, X of ABX), 2.95 (dd, 1H, A of ABX), 2.65 (d, 1H, B of ABX),2.45 (s, 3H).

A solution of4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-benzylacetate (1 g, 2.80 mmol) in ethanol (50 ml) and ethyl acetate (25 ml)was hydrogenated over 10% Pd/C (300 mg) for 2 hrs. After filtration oncelite and concentration in vacuo,4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid (790 mg, >100%%) was obtained as a white solid.

¹H NMR (d₆ DMSO): δ 9.90 (s, 1H), 7.35 (m, 1H), 7.20 (m, 1H), 6.95 (m,1H), 4.15 (d, 1H, X of ABX), 2.85 (dd, 1H, A of ABX), 2.40 (d, 1H, B ofABX), 2.30 (s, 3H).

EXAMPLE 114-(R,S)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid

To a solution of4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-benzylacetate (2 g, 5.6 mmol) in DMF (10 ml) was added dimethyl sulfate (0.64ml, 6.72 mmol) followed by sodium hydride (60% dispersion in oil, 246mg, 6.16 mmol) by portions. After stirring at room temperature for 15min, the reaction mixture was carefully quenched with water, dilutedwith 1N HCl, diethyl ether and ethyl acetate. The organic layer wasextracted, washed with saturated aqueous sodium bicarbonate and brine,dried over MgSO₄, and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 25% ethyl acetate inhexane to 35%) to provide4-(R,S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-benzylacetate (2.03 g, 98%) which was hydrogenated following a similarprocedure as described in example 5, to provide:4-(R,S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid as a white solid.

¹H NMR (CDCl₃): δ 7.10 (m, 1H), 6.96-6.80 (m, 2H), 4.20 (d, 1H, X ofABX), 3.25 (s, 3H), 2.95 (dd, 1H, A of ABX), 2.80 (d, 1H, B of ABX),2.60 (s, 3H).

EXAMPLE 12(−)-4-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid

4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-benzylacetate (example I) was resolved on Chiralcel OD (90:10:0.1hexane:ethanol:diethyl amine) to provide the (+) enantiomer (1stfraction, [a]_(D)=+68.4° (c=0.53, MeOH) and provide the (−) enantiomer(2nd fraction, [a]_(D)=−67.4° (c=0.39, MeOH). Both enantiomers werehydrogenated as described in example I, providing(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid ([a]_(D)=−80.4° (c=0.36, MeOH)) and its (+) enantiomer. The (+)enantiomer was converted to the less active (+) alpha-1 antagonistdescribed in example 18 (the S enantiomer) thus identifying(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid as the enantiomer leading to the more “active” alpha 1a antagonistby default.

EXAMPLE 13(+)-4-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid

(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-benzylacetate (Example 12) was methylated and hydrogenated using a similarprocedure as described in Example 11 to provide(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid:

[a]_(D)=+25.3° (c=0.40, MeOH).

EXAMPLES 14-33

The general procedure employed to prepare each of the compounds setforth in Examples 14-33 below was one of the following:

General Procedure A

To a solution of(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid (see Example 12) or(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid (see Example 13) (0.06 mmol) in DMF (0.1 ml) the following wereadded sequentially: triethyl amine (0.04 ml, 0.3 mmol), the primaryamine of interest, mono or dihydrochloride.(0.06 mmol),1-hydroxy-7-azabenzotriazole (8.2 mg, 0.06 mmol, in 0.25 ml DMF), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride 11.5 mg,0.06 mmol, in 0.45 ml DMF). The reaction mixture was stirred by vortexfor a few seconds and allowed to stand at room temperature for 16 hours.The crude mixture was purified by preparative reverse phase HPLC (C8,ACN, water, TFA). The products of interest were isolated as TFA saltsafter fraction selection and solvent evaporation. ¹H NMR, MS, andanalytical HPLC were used to assess identity and purity.

General Procedure B

To a solution of4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid (see Example 10) or4-(R,S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid (see Example 11) (0.5 mmol, 1 eq) in DMF (20 ml) the following wereadded sequentially: triethyl amine (4 eq), the primary amine ofinterest, mono or dihydrochloride.(0.8 eq), 1-hydroxy-7-azabenzotriazole(1 eq), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride(1 eq). The reaction mixture was stirred at room temperature for 16hours, diluted with ethyl acetate, washed with water, saturated aqueoussodium bicarbonate, water, and aqueous lithium chloride, dried overNa₂SO₄, and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 2% (10% NH₄OH/MeOH) in methylenechloride to 4%) to provide the corresponding amide, racemic, as a freebase or as the hydrochloride after treatment with 1 N HCl in diethylether.

The racemic material was resolved by preparative HPLC (Chiralpak AD orChiralcel OJ) to provide both enantiomers as free bases or as thehydrochlorides after treatment with 1 N HCl in diethyl ether.

EXAMPLE 144-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (see Example 1) and(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=469.25.

EXAMPLE 15 4-(R)-(3 ,4-Difluorophenyl)-1 ,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (see Example 1) and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=483.26.

EXAMPLE 164-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-pyridyl)-4-cyano-piperidin-1-yl]propylamine (prepared using aprocedure similar to that described in Example 4 above) and(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=494.24.

EXAMPLE 17 4-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-pyridyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-pyridyl)-4-cyano-piperidin-1-yl]propylamine (prepared using aprocedure similar to that described in Example 4 above) and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=508.26.

EXAMPLE 184-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(4-fluorophenyl)-piperidin-1-yl]propylamine (see Example 2) and4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=−60.8° (c=0.24,MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=+65.5° (c=0.2, MeOH).

EXAMPLE 194-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(4-fluorophenyl)-piperidin-1-yl]propylamine (see Example 7) and4-(R,S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=+10° (c=0.2, MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=−9.8° (c=0.18, MeOH).

EXAMPLE 204-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]propylamine (see Example 3)and(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=511.23.

EXAMPLE 214-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyano-4-fluorophenyl)-piperidin-1-yl]propylamine (see Example 3)and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H 525.25.

EXAMPLE 224-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(4-fluorophenyl)-4-cyano-piperidin-1-yl]propylamine (see Example 4)and4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=−55.6° (c=0.18,MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=+54.3° (c=0.18, MeOH).

EXAMPLE 234-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(4-fluorophenyl)-4-cyano-piperidin-1-yl]propylamine (see Example 4)and4-(R,S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=+5.9° (c=0.15,MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=−4.1° (c=0.17, MeOH).

EXAMPLE 244-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyano-4-fluorophenyl)-4-cyano-piperidin-1-yl]propylamine (seeExample 5) and(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=536.23.

EXAMPLE 254-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyano-4-fluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyano-4-fluorophenyl)-4-cyano-piperidin-1-yl]propylamine (seeExample 5) and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=550.24.

EXAMPLE 264-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2,4-difluorophenyl)-4-cyano-piperidin-1-yl]propylamine (seeExample 6) and4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=−56.7° (c=0.18,MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=+54° (c=0.17, MeOH).

EXAMPLE 274-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2,4-difluorophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2,4-difluorophenyl)-4-cyano-piperidin-1-yl]propylamine (seeExample 6) and4-(R,S)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=+5° (c=0.24, MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=−6° (c=0.18, MeOH).

EXAMPLE 284-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyanophenyl)-piperidin-1-yl]propylamine (see Example 7) and(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=493.24.

EXAMPLE 294-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyanophenyl)-piperidin-1-yl]propylamine (see Example 7) and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=507.26.

EXAMPLE 304-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyanophenyl)-4-cyano-piperidin-1-yl]propylamine (see Example 8)and(−)-4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=518.24.

EXAMPLE 314-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{3-[4-(2-cyanophenyl)-4-cyano-piperidine-1-yl]-propyl}amide

The title compound was prepared from3-[4-(2-cyanophenyl)-4-cyano-piperidin-1-yl]propylamine (see Example 8)and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=532.26.

EXAMPLE 324-(R)-(3,4-Difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide

The title compound was prepared from trans2-[4-(2-Amino-ethylamino)-cyclohexyl]-benzonitrile (see Example 9) and4-(R,S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure B. [α]_(D)=19.4° (c=0.11,MeOH).

The (S) enantiomer was also resolved from the racemate in the sameprocedure. [α]_(D)=+14.2° (c=0.09, MeOH).

EXAMPLE 334-(R)-(3,4-Difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide

The title compound was prepared trans2-[4-(2-Amino-ethylamino)-cyclohexyl]-benzonitrile (see Example 9) and(+)-4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid in accordance with General Procedure A.

MS: M+H=507.26.

EXAMPLE 34

As a specific embodiment of an oral composition, 100 mg of the compoundof Example 20 is formulated with sufficient finely divided lactose toprovide a total amount of 580 to 590 mg to fill a size O hard gelcapsule.

EXAMPLE 35 Screening Assay: Alpha 1a Adrenergic Receptor Binding

Membranes prepared from the stably transfected human alpha 1a cell line(ATCC CRL 11140) were used to identify compounds that bind to the humanalpha 1a adrenergic receptor. These competition binding reactions (totalvolume=200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl,100 pM [¹²⁵ I]-HEAT, membranes prepared from the alpha 1a cell line andincreasing amounts of unlabeled ligand. Reactions were incubated at roomtemperature for one hour with shaking. Reactions were filtered ontoWhatman GF/C glass fiber filters with a Inotec 96 well cell harvester.Filters were washed three times with ice cold buffer and boundradioactivity was determined (Ki).

EXAMPLE 36 Selective Binding Assays

Membranes prepared from stably transfected human alpha 1d and alpha 1bcell lines (ATCC CRL 11138 and CRL 11139, respectively) were used toidentify compounds that selectively bind to the human alpha 1aadrenergic receptor. These competition binding reactions (totalvolume=200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl,100 pM [¹²⁵ I]-HEAT, membranes prepared from cell lines transfected withthe respective alpha 1 subtype expression plasmid and increasing amountsof unlabeled ligand. Reactions were incubated at room temperature forone hour with shaking. Reactions were filtered onto Whatman GF/C glassfiber filters with a Inotec 96 well cell harvester. Filters were washedthree times with ice cold buffer and bound radioactivity was determined(Ki).

All of the compounds of the present invention prepared in the foregoingExamples were found to have alpha 1a Ki values of less than 50 nM asdetermined via the screening assay described in Example 35 , except forExample 17 (257 nM). All of the compounds were further found to be atleast about 10-fold more selective in binding to alpha 1a receptorsversus binding to the alpha 1b and alpha 1d receptors, as determined viathe selective binding assay described in the preceding paragraph, exceptfor Example 17 (1a about 8-fold more selective than 1b). All of thecompounds except for those of Examples 17, 32 and 33 were at least about40-fold more selective in binding to alpha 1a receptors versus alpha 1band 1d receptors.

EXAMPLE 37 Exemplary Counterscreens

1. Assay Title: Dopamine D2, D3, D4 in vitro screen

Objective of the Assay:

The objective of this assay is to eliminate agents which specificallyaffect binding of [3H] spiperone to cells expressing human dopaminereceptors D2, D3 or D4.

Method:

Modified from VanTol et al (1991); Nature (Vol 350) Pg 610-613.

Frozen pellets containing specific dopamine receptor subtypes stablyexpressed in clonal cell lines are lysed in 2 ml lysing buffer (10 mMTris-HCl/5 mM Mg, pH 7.4). Pellets obtained after centrifuging thesemembranes (15′ at 24,450 rpm) are resuspended in 50 mM Tris-HCl pH 7.4containing EDTA, MgCl[2], KCl, NaCl, CaCl[2] and ascorbate to give a 1Mg/mL suspension. The assay is initiated by adding 50-75 μg membranes ina total volume of 500 μl containing 0.2 nM [3H]-spiperone. Non-specificbinding is defined using 10 μM apomorphine. The assay is terminatedafter a 2 hour incubation at room temperature by rapid filtration overGF/B filters presoaked in 0.3% PEI, using 50 mM Tris-HCl pH 7.4.

2. Assay Title: Serotonin 5HT1a

Objective of the Assay

The objective of this assay is to eliminate agents which specificallyaffect binding to cloned human 5HT1a receptor

Method:

Modified from Schelegel and Peroutka Biochemical Pharmacology 35:1943-1949 (1986).

Mammalian cells expressing cloned human 5HT1a receptors are lysed inice-cold 5 mM Tris-HCl, 2 mM EDTA (pH 7.4) and homogenized with apolytron homogenizer. The homogenate is centrifuged at 1000×g for 30′,and then the supernatant is centrifuged again at 38,000×g for 30′. Thebinding assay contains 0.25 riM [3H]8-OH-DPAT(8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) in 50 mMTris-HCl, 4 mM CaCl2 and 1 mg/ml ascorbate. Non-specific binding isdefined using 10 μM propranolol. The assay is terminated after a 1 hourincubation at room temperature by rapid filtration over GF/Cfilters

EXAMPLE 38 Exemplary Functional Assays

In order to confirm the specificity of compounds for the human alpha 1aadrenergic receptor and to define the biological activity of thecompounds, the following functional tests may be performed:

1. In vitro Rat, Dog and Human Prostate and Dog Urethra

Taconic Farms Sprague-Dawley male rats, weighing 250-400 grams aresacrificed by cervical dislocation under anesthesia (methohexital; 50mg/kg, i.p.). An incision is made into the lower abdomen to remove theventral lobes of the prostate. Each prostate removed from a mongrel dogis cut into 6-8 pieces longitudinally along the urethra opening andstored in ice-cold oxygenated Krebs solution overnight before use ifnecessary. Dog urethra proximal to prostate is cut into approximately 5mm rings, the rings are then cut open for contractile measurement ofcircular muscles. Human prostate chips from transurethral surgery ofbenign prostate hyperplasia are also stored overnight in ice-cold Krebssolution if needed.

The tissue is placed in a Petri dish containing oxygenated Krebssolution [NaCl, 118 mM; KCl, 4.7 mM; CaCl₂, 2.5 mM; KH₂PO₄, 1.2 mM;MgSO₄, 1.2 mM; NaHCO₃, 2.0 mM; dextrose, 11 mM] warmed to 37° C. Excesslipid material and connective tissue are carefully removed. Tissuesegments are attached to glass tissue holders with 4-0 surgical silk andplaced in a 5 ml jacketed tissue bath containing Krebs buffer at 37° C.,bubbled with 5% CO₂/95% O₂. The tissues are connected to a Statham-Gouldforce transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension isapplied and the tissues are allowed to equilibrate for one hour.Contractions are recorded on a Hewlett-Packard 7700 series strip chartrecorder.

After a single priming dose of 3 μM (for rat), 10 μM (for dog) and 20 μM(for human) of phenylephrine, a cumulative concentration response curveto an agonist is generated; the tissues are washed every 10 minutes forone hour. Vehicle or antagonist is added to the bath and allowed toincubate for one hour, then another cumulative concentration responsecurve to the agonist is generated.

EC₅₀ values are calculated for each group using GraphPad Inplotsoftware. pA₂ (−log K_(b)) values were obtained from Schild plot whenthree or more concentrations were tested. When less than threeconcentrations of antagonist are tested, K_(b) values are calculatedaccording to the following formula

K_(b)=[B],

where x is the ratio of EC₅₀ of agonist in the presence and absence ofantagonist and [B] is the antagonist concentration.

2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs

PURPOSE: Benign prostatic hyperplasia causes a decreased urine flow ratethat may be produced by both passive physical obstruction of theprostatic urethra from increased prostate mass as well as activeobstruction due to prostatic contraction. Alpha adrenergic receptorantagonists such as prazosin and terazosin prevent active prostaticcontraction, thus improve urine flow rate and provide symptomatic reliefin man. However, these are non-selective alpha 1 receptor antagonistswhich also have pronounced vascular effects. Because we have identifiedthe alpha 1a receptor subtype as the predominant subtype in the humanprostate, it is now possible to specifically target this receptor toinhibit prostatic contraction without concomitant changes in thevasculature. The following model is used to measure adrenergicallymediated changes in intra-urethral pressure and arterial pressure inanesthetized dogs in order to evaluate the efficacy and potency ofselective alpha adrenergic receptor antagonists. The goals are to: 1)identify the alpha 1 receptor subtypes responsible forprostatic/urethral contraction and vascular responses, and 2) use thismodel to evaluate novel selective alpha adrenergic antagonists. Noveland standard alpha adrenergic antagonists may be evaluated in thismanner.

METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogsare anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4mg/kg/hr iv infusion). An endotracheal tube is inserted and the animalventilated with room air using a Harvard instruments positivedisplacement large animal ventilator. Catheters (PE 240 or 260) areplaced in the aorta via the femoral artery and vena cava via the femoralveins (2 catheters, one in each vein) for the measurement of arterialpressure and the administration of drugs, respectively. A supra-pubicincision ˜½ inch lateral to the penis is made to expose the urethers,bladder and urethra. The urethers are ligated and cannulated so thaturine flows freely into beakers. The dome of the bladder is retracted tofacilitate dissection of the proximal and distal urethra. Umbilical tapeis passed beneath the urethra at the bladder neck and another piece ofumbilical tape is placed under the distal urethra approximately 1-2 cmdistal to the prostate. The bladder is incised and a Millar micro-tippressure transducer is advanced into the urethra. The bladder incisionis sutured with 2-0 or 3-0 silk (purse-string suture) to hold thetransducer. The tip of the transducer is placed in the prostatic urethraand the position of the Millar catheter is verified by gently squeezingthe prostate and noting the large change in urethral pressure.

Phenylephrine, an alpha 1 adrenergic agonist, is administered (0.1-100ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curvesfor changes in intra-urethral and arterial pressure. Followingadministration of increasing doses of an alpha adrenergic antagonist (orvehicle), the effects of phenylephrine on arterial pressure andintra-urethral pressure are re-evaluated. Four or five phenylephrinedose-response curves are generated in each animal (one control, three orfour doses of antagonist or vehicle). The relative antagonist potency onphenylephrine induced changes in arterial and intra-urethral pressureare determined by Schild analysis. The family of averaged curves are fitsimultaneously (using ALLFIT software package) with a four paramenterlogistic equation constraining the slope, minimum response, and maximumresponse to be constant among curves. The dose ratios for the antagonistdoses (rightward shift in the dose-response curves from control) arecalculated as the ratio of the ED₅₀'s for the respective curves. Thesedose-ratios are then used to construct a Schild plot and the Kb(expressed as ug/kg, iv) determined. The Kb (dose of antagonist causinga 2-fold rightward shift of the phenylephrine dose-response curve) isused to compare the relative potency of the antagonists on inhibitingphenylephrine responses for intra-urethral and arterial pressure. Therelative selectivity is calculated as the ratio of arterial pressure andintra-urethral pressure Kb's. Effects of the alpha 1 antagonists onbaseline arterial pressure are also monitored. Comparison of therelative antagonist potency on changes in arterial pressure andintra-urethral pressure provide insight as to whether the alpha receptorsubtype responsible for increasing intra-urethral pressure is alsopresent in the systemic vasculature. According to this method, one isable to confirm the selectivity of alpha 1a adrenergic receptorantagonists that prevent the increase in intra-urethral pressure tophenylephrine without any activity at the vasculature.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

What is claimed is:
 1. A compound of formula

wherein Y is CH; X is NR⁶; R¹ is phenyl, mono- or poly-substitutedphenyl, naphthyl, mono- or poly-substituted naphthyl, heterocyclic, ormono- or poly-substituted heterocyclic; wherein the heterocyclic isselected from the group consisting of pyridyl, pyrazinyl, thienyl,thiazolyl, furanyl and quinazolinyl; each of the substituents on thesubstituted phenyl or substituted naphthyl is independently selectedfrom halo, nitro, cyano, hydroxy, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆alkoxy, halogenated C₁-C₆ alkyl, halogenated C₃-C₈ cycloalkyl,halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and(CH₂)₀₋₄SO₂R^(c); and each of the substitutents on the substitutedheterocyclic is independently selected from halo, cyano, nitro,N(R^(c))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), phenyl, C₁-C₆ alkyl, halogenatedC₁-C₆ alkyl, C₁-C₆ alkoxy, halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(a),C₃-C₈ cycloalkyl, and halogenated C₃-C₈ cycloalkyl; R² is hydrogen,cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂, tetrazole,isooxadiazole, phenyl, mono- or poly-substituted phenyl, naphthyl, mono-or poly-substituted naphthyl, heterocyclic, or mono- or poly-substitutedheterocyclic; wherein the heterocyclic is selected from the groupconsisting of pyridyl, thienyl and furanyl; each of the substituents onthe substituted phenyl or substituted naphthyl is independently selectedfrom halo, cyano, nitro, hydroxy, C₁-C₆ alkoxy, halogenated C₁-C₆alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, C₃-C₈ cycloalkyl, and halogenated C₃-C₈cycloalkyl; and each of the substituents on the substituted heterocyclicis independently selected from halo, (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), phenyl,C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, C₁-C₆ alkoxy, halogenated C₁-C₆alkoxy, (CH₂)₁₋₄OR^(a), C₃-C₈ cycloalkyl, and halogenated C₃-C₈cycloalkyl; each R³ is a substituent connected to a ring atom other thanCR¹R² or Y and is independently C₁-C₄ alkyl; R⁴ and R⁵ are eachindependently selected from hydrogen, C₁-C₆ alkyl, and C₃-C₈ cycloalkyl;R⁶ is hydrogen or C₁-C₄ alkyl; R⁷ is phenyl, or mono- orpoly-substituted phenyl; wherein each of the substituents on thesubstituted phenyl is independently selected from halo, nitro, cyano,hydroxy, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy, halogenated C₁-C₆alkyl, halogenated C₃-C₈ cycloalkyl, halogenated C₁-C₆ alkoxy,(CH₂)₁₋₄OR^(b), N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂,NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); R⁸is hydrogen, C₁-C₆ alkyl, (CH₂)₀₋₄CO₂R^(c), or (CH₂)₀₋₄C(═O)R^(c); R⁹ ishydrogen, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy,halogenated C₁-C₆ alkyl, halogenated C₃-C₈ cycloalkyl, halogenated C₁-C₆alkoxy, (CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂; R^(a)is hydrogen, C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl; R^(b) is hydrogen,C₁-C₆ alkyl, or halogenated C₁-C₆ alkyl; R^(c) and R^(d) are eachindependently selected from hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl and(CH₂)₁₋₄CF₃; m is an integer of from 0 to 2; n is an integer of from 2to 4; o is zero; and p and q are each integers of from 0 to 2, whereinthe sum of p+q is less than or equal to 3; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1, whereinR¹ is phenyl, mono- or di-substituted phenyl, naphthyl, mono- ordi-substituted naphthyl, heterocyclic, or mono- or di-substitutedheterocyclic; R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c),C(═O)N(R^(c))₂, tetrazole, isooxadiazole, phenyl, mono- ordi-substituted phenyl, naphthyl, mono- or di-substituted naphthyl,heterocyclic, or mono- or di-substituted heterocyclic; and R⁷ isselected from phenyl, or mono- or di-substituted phenyl; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R¹ is phenyl, mono- or di-substituted phenyl, pyridyl,or mono- or di-substituted pyridyl; wherein each of the substituents onthe substituted phenyl is independently selected from halo, cyano,hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenatedC₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and(CH₂)₀₋₄SO₂R^(c); and each of the substituents on the substitutedpyridyl is independently selected from halo, cyano, N(R^(c))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂,(CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy,halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a); R² is hydrogen, cyano,hydroxy, C₁-C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂, phenyl, mono- ordi-substituted phenyl, pyridyl, or mono- or di-substituted pyridyl;wherein each of the substituents on the substituted phenyl isindependently selected from halo, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy,(CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); and eachof the substituents on the substituted pyridyl is independently selectedfrom halo, C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, C₁-C₄ alkoxy,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); R⁷is phenyl, or mono- or poly-substituted phenyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄alkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c),C(═O)N(R^(c))₂, SO₂N(R^(c))₂, and SO₂R^(c); R^(a) is hydrogen, C₁-C₄alkyl, or halogenated C₁-C₄ alkyl; R^(b) is hydrogen, C₁-C₄ alkyl, orhalogenated C₁-C₄ alkyl; and R^(c) and R^(d) are each independentlyselected from hydrogen, C₁-C₄ alkyl and (CH₂)₁₋₂CF₃; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1, wherein R¹ is phenyl, or mono- or di-substituted phenyl,pyridyl, or mono- or di-substituted pyridyl; wherein each of thesubstituents on the substituted phenyl is independently selected fromhalo, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄alkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); and each of the substituentson the substituted pyridyl is independently selected from halo, cyano,N(R^(c))₂, (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂,(CH₂)₀₋₄SO₂N(R^(c))₂, (CH₂)₀₋₄SO₂R^(c), C₁-C₄ alkyl, halogenated C₁-C₄alkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkoxy, and (CH₂)₁₋₄OR^(a); R² ishydrogen, cyano, hydroxy, C₁-C₆ alkoxy, CO₂R^(c), or C(═O)N(R^(c))₂; R⁴and R⁵ are either both hydrogen, or one of R⁴ and R⁵ is hydrogen and theother is hydrogen, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl; R⁷ is phenyl, ormono- or di-substituted phenyl; wherein each of the substituents on thesubstituted phenyl is independently selected from halo, cyano, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), (CH₂)₀₋₄CF₃, OCF₃, N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c),C(═O)N(R^(c))₂, SO₂N(R^(c))₂, and SO₂R^(c); and R^(b) is C₁-C₄ alkyl orCF₃; or a pharmaceutically acceptable salt thereof.
 5. The compoundaccording to claim 1, wherein the compound is of formula

wherein A is CR¹⁰ or N; R² is hydrogen, cyano, hydroxy, C₁-C₆ alkoxy,CO₂R^(c), C(═O)N(R^(c))₂, phenyl, or mono- or poly-substituted phenyl;wherein each of the substituents on the substituted phenyl isindependently selected from halo, cyano, nitro, hydroxy, C₁-C₆ alkyl,halogenated C₁-C₆ alkyl, C₁-C₆ alkoxy, halogenated C₁-C₆ alkoxy,(CH₂)₁₋₄OR^(a), (CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, and (CH₂)₀₋₄SO₂R^(c); R⁸ ishydrogen, C₁-C₄ alkyl, (CH₂)₀₋₄CO₂R^(c), or (CH₂)₀₋₄C(═O)R^(c); R⁹ ishydrogen, halo, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy,halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy, (CH₂)₁₋₄OR^(b),CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂; each R¹⁰ is independentlyhydrogen, halo, nitro, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂,(CH₂)₀₋₄CO₂R^(c), (CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, or(CH₂)₀₋₄SO₂R^(c); each R¹² is independently hydrogen, halo, nitro,cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, halogenatedC₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl, halogenated C₁-C₄ alkoxy,(CH₂)₁₋₄OR^(b), N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂,NR^(c)SO₂R^(d), NR^(c)SO₂N(R^(d))₂, (CH₂)₀₋₄CO₂R^(c),(CH₂)₀₋₄C(═O)N(R^(c))₂, (CH₂)₀₋₄SO₂N(R^(c))₂, or (CH₂)₀₋₄SO₂R^(c); n isan integer of from 2 to 4; and r and s are independently integers offrom 0 to 2; or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 5, wherein the compound is a (+) enantiomer;or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 5, wherein the compound is a (−) enantiomer; or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 5, wherein R² is hydrogen, cyano, hydroxy, C₁-C₄ alkoxy, CO₂R^(c),C(═O)N(R^(c))₂, phenyl, or mono- or poly-substituted phenyl; whereineach of the substituents on the substituted phenyl is independentlyselected from halo, cyano, hydroxy, C₁-C₄ alkyl, halogenated C₁-C₄alkyl, C₁-C₄ alkoxy, halogenated C₁C₄ alkoxy, CO₂R^(c), C(═O)N(R^(c))₂,N(R^(c))₂, NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d),SO₂N(R^(c))₂, and SO₂R^(c); R⁸ is hydrogen, C₁-C₄ alkyl, CO₂R^(c), orC(═O)R^(c); R⁹ is hydrogen, halo, cyano, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy,(CH₂)₁₋₄OR^(b), CO₂R^(c), C(═O)R^(c), or C(═O)N(R^(c))₂; each R¹⁰ isindependently hydrogen, halo, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆cycloalkyl, halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(a), N(R^(c))₂,NR^(c)C(═O)R^(d), NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c),C(═O)N(R^(c))₂, SO₂N(R^(c))₂, or SO₂R^(c); each R¹² is independentlyhydrogen, halo, cyano, hydroxy, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, halogenated C₁-C₄ alkyl, halogenated C₃-C₆ cycloalkyl,halogenated C₁-C₄ alkoxy, (CH₂)₁₋₄OR^(b), N(R^(c))₂, NR^(c)C(═O)R^(d),NR^(c)C(═O)N(R^(d))₂, NR^(c)SO₂R^(d), CO₂R^(c), C(═O)N(R^(c))₂,SO₂N(R^(c))₂, or SO₂R^(c); R^(a) is hydrogen, C₁-C₄ alkyl, orhalogenated C₁-C₄ alkyl; R^(b) is hydrogen, C₁-C₄ alkyl, or halogenatedC₁-C₄ alkyl; and R^(c) and R^(d) are each independently selected fromhydrogen and C₁-C₄ alkyl; or a pharmaceutically acceptable salt thereof.9. The compound according to claim 8, wherein R² is hydrogen, cyano,hydroxy, C₁-C₄ alkoxy, CO₂R^(c), or C(═O)N(R^(c))₂; or apharmaceutically acceptable salt thereof.
 10. The compound according toclaim 9, wherein the compound is selected from the group consisting of4-(R)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide;4-(S)-(3,4-difluorophenyl)-6-methyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide;4-(R)-(3,4-difluorophenyl)-1,6-dimethyl-3,4-dihydro-2-pyridinone-5-carboxylicacid{2-[4-(2-cyanophenyl)-cyclohexylamine-N-yl]-ethyl}amide; andpharmaceutically acceptable salts thereof.
 11. A pharmaceuticalcomposition comprising the compound according to claim 1 and apharmaceutically acceptable carrier.
 12. A pharmaceutical compositionmade by combining the compound according to claim 1 and apharmaceutically acceptable carrier.
 13. A process for making apharmaceutical composition comprising combining the compound accordingto claim 1 and a pharmaceutically acceptable carrier.
 14. Thecomposition according to claim 11 further comprising a testosterone5-alpha reductase inhibitor.
 15. The composition according to claim 14,wherein the testosterone 5-alpha reductase inhibitor is a type 1, a type2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone5-alpha reductase inhibitor.
 16. The composition according to claim 15,wherein the testosterone 5-alpha reductase inhibitor is a type 2testosterone 5-alpha reductase inhibitor.
 17. The composition accordingto claim 16, wherein the testosterone 5-alpha reductase inhibitor isfinasteride.
 18. A method of treating benign prostatic hyperplasia in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of the compound according to claim 1.19. The method according to claim 18, wherein the compound does notcause a fall in blood pressure at dosages effective to alleviate benignprostatic hyperlasia.
 20. The method according to claim 18, wherein thecompound is administered in combination with a testosterone 5-alphareductase inhibitor.
 21. The method according to claim 20, wherein thetestosterone 5-alpha reductase inhibitor is finasteride.
 22. A method oftreating benign prostatic hyperplasia in a subject in need thereof whichcomprises administering a therapeutically effective amount of thecomposition according to claim
 11. 23. The method according to claim 22,wherein the composition further comprises a therapeutically effectiveamount of a testosterone 5-alpha reductase inhibitor.
 24. A method ofrelaxing lower urinary tract tissue in a subject in need thereof whichcomprises administering to the subject a therapeutically effectiveamount of the compound according to claim
 1. 25. The method according toclaim 24, wherein the compound is administered in combination with atestosterone 5-alpha reductase inhibitor.
 26. The method according toclaim 25, wherein the testosterone 5-alpha reductase inhibitor isfinasteride.
 27. A method of treating a condition which is in need ofalpha 1a adrenergic receptor antagonism in a subject comprisesadministering to said subject an amount of a compound according to claim1 effective to treat said condition.
 28. A method of eliciting an alpha1a adrenergic receptor antagonizing effect in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of the compound according to claim 1.